1-cyclohexyl-2-phenylaminobenzimidazoles as midh1 inhibitors for the treatment of tumors

ABSTRACT

The present invention relates to benzimidazol-2-amines of general formula (I) in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11  and R 12  are as defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.

The present invention relates to benzimidazol-2-amine compounds ofgeneral formula (I) as described and defined herein, to methods ofpreparing said compounds, to intermediate compounds useful for preparingsaid compounds, to pharmaceutical compositions and combinationscomprising said compounds and to the use of said compounds formanufacturing a pharmaceutical composition for the treatment orprophylaxis of a disease, in particular of neoplasms, as a sole agent orin combination with other active ingredients.

BACKGROUND OF THE INVENTION

The present invention relates to chemical compounds that inhibit mutatedisocitratdehydrogenase 1 (mIDH1 R132H), to methods of preparing saidcompounds, to pharmaceutical compositions and combinations comprisingsaid compounds, to the use of said compounds for manufacturing apharmaceutical composition for the treatment or prophylaxis of adisease, as well as to intermediate compounds useful in the preparationof said compounds.

Isocitrate dehydrogenases (IDH) are key enzymes in cellular metabolism,converting isocitrate to alpha-ketoglutarate and belong to 2 subgroups,defined by the utilization of different electron receptor. Two of them,isocitrate dehydrogenase 1 and 2 use NADP(+) as electron receptor. IDH1is located in the cytoplasm and peroxisomes and IDH2 in the mitochondriaas an integral part of the TCA cycle, e.g in the following reaction:

Isocitrate+NADP⁺→alpha-ketoglutarate+CO₂+NADPH+H⁺

Both enzymes act as homodimers.

In a variety of tumor entities, including glioma, acute myeloid leukemia(AML), chondrosarcoma, cholangiocarcinoma, melanoma, prostate cancer,angioimmunoblastic T-cell lymphoma and others, IDH1 or IDH2 are mutatedat a distinct amino acid position (Balss J. Acta Neuropathol. 2008December; 116(6):597-602, Mardis E R, N Engl J Med. Sep. 10, 2009;361(11):1058-66, Amary M F, J Pathol. 2011 July; 224(3):334-43, Borger DR, Oncologist. 2012; 17(1):72-9, Shibata T, Am J Pathol. 2011 March;178(3):1395-402, Ghiam A F, Oncogene. Aug. 16, 2012; 31(33):3826, CairnsR A, Blood. Feb. 23, 2012; 119(8):1901-3). This mutation is alwaysheterozygous and mutual exclusive. Most of these point mutations havebeen found at key positions in the catalytic domain of the enzyme(responsible 2-oxoglutarate coordination), e.g. IDH1R100, IDH1R132,IDH1G97 and IDH₂R^(140,) IDH₂R172 (Dang L., Nature, Dec. 10, 2009;462(7274):739-44). In glioma, more than 70% of all non-primaryglioblastoma are IDH1 mutated and in 92.7% of the IDH1 mutated tumorsthe arginine was replaced by a histidine (IDH1R132H). (Hartmann C, ActaNeuropathol. 2009 October; 118(4):469-74).

The replacement of the wildtype amino acid at those catalytic residuesleads to a neomorphic activity of the enzyme, convertingalpha-ketoglutarate to R-2-hydroxyglutarate (2-HG). 2-HG is metabolicwaste, but also an oncometabolite and it is believed to contribute totumorgenesis (Dang L., Nature, Dec. 10, 2009; 462(7274):739-44) 2-HG isonly produced in very low levels in normal cells, but cells harboringthe IDH mutations produce high levels of 2-HG. High amounts of 2-HG havealso been found in tumors with the IDH mutation. IDH mutations have alsobeen described in patient with other disorders with high 2-HG levels,e.g. in a rare neurometabolic disorder characterized bysupraphysiological levels of 2-HG (2-HG aciduria) (Kranendijk M,Science. Oct. 15, 2010; 330(6002):336).

Hence, the inhibition of IDH mutations and its neomorphic activity is apotential therapeutic treatment option for tumors and other IDH mutationrelated disorders.

WO02/092575A1 relates to benzimidazole compounds as inhibitors ofmembrane fusion associated events, such as transfusion.

WO03/007945A1 and WO02/04425A2 relates inter alia to benzimidazolecompounds as inhibitors of RNA dependent RNA polymerases.

WO2009/059214A1 relates to Aβ-binding benzimidazole derivatives.

WO2008/153701A1 relates to benzimidazole compounds as inhibitors of KSPkinesin activity.

WO2005/121132A1 relates to fused heterocyclic compounds having anti-HCVeffect.

EP0385850A2 discloses benzimidazole and azabenzimidazole derivatives forthe treatment of cardiovascular diseases and duodenal ulcers.

WO00/32578 A1 discloses benzimidazole compounds as vitronectin receptorantagonists.

WO2004/085425A1 discloses inter alia benzimidazole compounds havingVEGFR/KDR inhibitory activity.

EP1810677A1 discloses benzimidazole compounds as GPR40 receptor functionregulators.

EP1069124A1 discloses 2-benzimidazolylamine compounds as ORL1-receptoragonists.

WO2010/034796A1 discloses benzimidazole compounds as inhibitors ofenzymes belonging to the membrane-assiciated proteins in the eicosanoidand gluthathione metabolism family.

WO2009/116074A2 discloses substituted benzimidazoles as cannabinoidmodulators.

WO03/074515A1 discloses benzimidazole derivatives as TIE-2 and/orVEGFR-2 inhibitors.

WO2005/044793A2 discloses inter alia benzimidazole compounds as CRFreceptor antagonists.

WO2006/099379A2 discloses benzazole derivatives as beta-secretaseinhibitors.

WO2010/100249A1 discloses inter alia benzimidazole compounds asinhibitors of the microsomal prostaglandin E2 synthase-1.

However, the state of the art described above does not describe thespecific substituted benzimidazole compounds of general formula (I) ofthe present invention as defined herein, or a stereoisomer, a tautomer,an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture ofsame, as described and defined herein, and as hereinafter referred to as“compounds of the present invention”, or their pharmacological activity.

It has now been found, and this constitutes the basis of the presentinvention, that said compounds of the present invention have surprisingand advantageous properties.

In particular, said compounds of the present invention have been foundto effectively inhibit mutated isocitratdehydrogenase 1 (mIDH1 R132H)and may therefore be used for the treatment or prophylaxis of diseasesof uncontrolled cell growth, proliferation and/or survival,inappropriate cellular immune responses, or inappropriate cellularinflammatory responses or diseases which are accompanied withuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses, for example, haematological tumours, solid tumours, and/ormetastases thereof, e.g. leukaemias and myelodysplastic syndrome,malignant lymphomas including angioimmunoblastic T-cell lymphomas, headand neck tumours including brain tumours and brain metastases (e.g.anaplastic astrocytoma, diffuse astrocytoma, glioblastoma,oligodendroglioma, secondary glioblastoma multiforme), tumours of thethorax including non-small cell and small cell lung tumours,gastrointestinal tumours including cholangiocarcinoma, endocrinetumours, mammary and other gynaecological tumours, urological tumoursincluding renal, bladder and prostate tumours, skin tumours, andsarcomas including chondrosarcomas, and/or metastases thereof.

DESCRIPTION OF THE INVENTION

In accordance with a first aspect, the present invention coverscompounds of general formula (I):

in which:

-   R¹ represents a halogen atom or group selected from:    -   C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,        cyano, (C₁-C₆-alkyl)-S—, and (C₁-C₆-haloalkyl)-S—;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a phenyl or heteroaryl group; wherein said group is    optionally substituted, with one or more substituents, which are    independently of each other selected from:    -   halo-, cyano, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl,        C₁-C₆-haloalkoxy, nitro, R¹³O—, R¹³S—, R¹³OC(═O)—(C₁-C₆-alkyl),        R¹³OC(═O)—(C₂-C₆-alkenyl), R¹³OC(═O)—(C₁-C₆-alkoxy)-,        R¹⁴(R¹⁶)NC(═O)—(C₁-C₆-alkyl)-, R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-, (C₁-C₆-alkyl)-S—,        (C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂-,        (C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³, —C(═O)N(R¹⁴)R₁₅,        —C(═O)N(R¹⁴)S(═O)₂R¹⁶, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶,        —N(R¹⁴)C(═O)R¹⁷, —N(R¹⁴)S(═O)₂R¹⁶, —S(═O)₂OR¹³, and        —S(═O)₂N(R¹⁴)R¹⁵;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from:    -   C₁-C₆-alkyl, and C₁-C₆-alkoxy;-   R⁷ represents a hydrogen atom;-   R⁸ represents a C₁-C₃-alkyl group;-   R⁹, R¹⁰, and R¹¹    -   are independently of each other selected from: hydrogen and        C₁-C₃-alkyl;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a group selected from:    C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-, and    (C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-,        (C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-, C₁-C₆-haloalkyl,        H₂N-(C₂-C₆-alkyl)-, (C₁-C₃-alkyl)N(H)(C₂-C₆-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-, R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to        6-membered heterocycloalkyl, phenyl, heteroaryl,        phenyl-(C₁-C₆-alkyl)-, and heteroaryl-(C₁-C₆-alkyl)-;    -   wherein phenyl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,        C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and —C(═O)NH₂;-   or-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl;    -   said 4-6-membered heterocycloalkyl being optionally substituted        with one substituent selected from: C₁-C₃-alkyl,        C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,        C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, halogen,        and cyano;    -   or said 4-6-membered heterocycloalkyl being optionally        substituted with one or two halogen atoms;-   R¹⁶ represents a hydrogen atom or a group selected from:    C₁-C₆-alkyl, HO—(C₁-C₆-alkyl)-, C₃-C₆-cycloalkyl,    HO—(C₃-C₆-cycloalkyl)-, C₁-C₆-haloalkyl,    (C₁-C₃-alkoxy)-(C₁-C₆-alkyl), phenyl, heteroaryl, and 4- to    6-membered heterocycloalkyl;    -   wherein phenyl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,        C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and        —C(═O)N(R¹⁴)R¹⁵;-   R¹⁷ represents a group selected from: —N(R¹⁴)R¹⁵ and C₁-C₆-alkoxy;-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

The terms as mentioned in the present text have preferably the followingmeanings:

The term “halogen atom”, “halo-” or “Hal-” is to be understood asmeaning a fluorine, chlorine, bromine or iodine atom.

The term “C₁-C₆-alkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group having 1, 2,3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl,hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl,2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl,neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl,3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or anisomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms(“C₁-C₄-alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl,iso-butyl, sec-butyl, tert-butyl group, more particularly 1, 2 or 3carbon atoms (“C₁-C₃-alkyl”), e.g. a methyl, ethyl, n-propyl- oriso-propyl group.

The term “-C₁-C₈-alkylene-” is understood as preferably meaning abivalent, linear or branched, saturated hydrocarbon chain (or “tether”)having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, e.g. —CH₂— (“methylene” or“-C₁-alkylene-”) or, for example —CH₂-CH₂- (“ethylene”or“-C₂-alkylene-”), —CH₂—CH₂—CH₂—, —C(H)(CH₃)-CH₂— or —C(CH₃)₂—(“propylene” or “-C₃-alkylene-”), or, for example —CH₂—C(H)(CH₃)-CH₂—,—CH₂—C(CH₃)₂-), —CH₂—CH₂—CH₂—CH₂— (“butylene” or “-C₄-alkylene-”),“-C₅-alkylene-”, e.g. —CH₂—CH₂—CH₂—CH₂—CH₂— (“n-pentylene”), or“-C₆-alkylene-”, e.g. —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂— (“n-hexylene”) group.Particularly, said alkylene tether has 1, 2, 3, 4, or 5 carbon atoms(“-C₁-C₅-alkylene-”), more particularly 1 or 2 carbon atoms(“-C₁-C₂-alkylene-”), or, 3, 4, or 5 carbon atoms (“-C₃-C₅-alkylene-”).

The term “C₁-C₆-haloalkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group in which theterm “C₁-C₆-alkyl” is defined supra, and in which one or more hydrogenatom is replaced by a halogen atom, in identically or differently, i.e.one halogen atom being independent from another. Particularly, saidhalogen atom is F. Said C₁-C₆-haloalkyl group is, for example, —CF₃,—CHF₂, —CH₂F, —CF₂CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, or CH₂CH₂CF₃.

The term “C₁-C₆-alkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent, group of formula—O—(C₁-C₆-alkyl), in which the term “C₁-C₆-alkyl” is defined supra, e.g.a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or anisomer thereof.

The term “C₁-C₆-haloalkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent C₁-C₆-alkoxy group, as definedsupra, in which one or more of the hydrogen atoms is replaced, inidentically or differently, by a halogen atom. Particularly, saidhalogen atom is F. Said C₁-C₆-haloalkoxy group is, for example, —OCF₃,—OCHF₂, —OCH₂F, —OCF₂CF₃, or —OCH₂CF₃.

The term “C₂-C₆-alkenyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group, which contains one ormore double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms,particularly 2 or 3 carbon atoms (“C₂-C₃-alkenyl”), it being understoodthat in the case in which said alkenyl group contains more than onedouble bond, then said double bonds may be isolated from, or conjugatedwith, each other. Said alkenyl group is, for example, a vinyl, allyl,(E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl,(Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl,(E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl,(E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl,(Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl,(Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl,2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl,(E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl,2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl,(E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl,(Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl,(E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl,(Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl,1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl,3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl,4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl,(E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl,(E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl,(E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl,(E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl,(E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl,(E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl,(E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl,(E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl,(E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl,(E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl,2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl,(Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl,(E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl,(Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl,(Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl,2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl,(Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl,(Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl,(Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl,(Z)-1-isopropylprop-1-enyl, (E)-3,3-dimethylprop-1-enyl,(Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl,buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienylgroup. Particularly, said group is vinyl or allyl.

The term “C₃-C₆-cycloalkyl” is to be understood as meaning a saturated,monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6carbon atoms. Said C₃-C₆-cycloalkyl group is for example, a monocyclichydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl ring.

The term “C₃-C₆-cycloalkyloxy” is to be understood as meaning asaturated, monovalent, monocyclic hydrocarbon group of formula—O—(C₃-C₆-cycloalkyl), in which the term “C₃-C₆-cycloalkyl” is definedsupra, e.g. a. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy orcyclohexyloxy group.

The term “4- to 6-membered heterocycloalkyl”, is to be understood asmeaning a saturated, monovalent, monocyclic hydrocarbon ring whichcontains 3, 4 or 5 carbon atoms, and one or two heteroatom-containinggroups selected from: O, S, S(═O), S(═O)₂, NH, and C(═O); wherein a4-membered heterocycloalkyl group contains only oneheteroatom-containing group selected from: O, S, S(═O), S(═O)₂, NH, andC(═O). Said 4- to 6-membered heterocycloalkyl group is attached to therest of the molecule via any one of the carbon atoms or, if present, anitrogen atom.

Particularly, without being limited thereto, said heterocycloalkyl canbe a 4-membered ring, such as azetidinyl or oxetanyl, or a 5-memberedring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl,imidazolidinyl or pyrazolidinyl, or a 6-membered ring, such astetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinylor piperazinyl.

The term “heteroaryl” is understood as preferably meaning a monovalent,monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7,8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl”group), particularly 5 or 6 or 9 or 10 atoms, and which contains atleast one heteroatom which may be identical or different, saidheteroatom being such as oxygen, nitrogen or sulfur, and in addition ineach case can be benzocondensed. Particularly, heteroaryl is selectedfrom: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, thia-4H-pyrazolyl, benzofuranyl, benzothienyl,benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl,indolyl, isoindolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, quinolinyl, quinazolinyl, isoquinolinyl, azocinyl,indolizinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, and oxepinyl.

In general, and unless otherwise mentioned, the heteroaryl groupincludes all the possible isomeric forms thereof, e.g. the positionalisomers thereof. Thus, for some illustrative non-restricting example,the term pyridinyl includes pyridin-2-yl, pyridin-3-yl, andpyridin-4-yl; or the term thienyl includes thien-2-yl, and thien-3-yl.

The term “C₁-C₆”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₆-alkyl”, “C₁-C₆-haloalkyl”, “C₁-C₆-alkoxy”, or“C₁-C₆-haloalkoxy” is to be understood as meaning an alkyl group havinga finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6carbon atoms. It is to be understood further that said term “C₁-C₆” isto be interpreted as any sub-range comprised therein, e.g. C₁-C₆, C₂-C₅,C₃-C₄, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, particularly C₁-C₂, C₁-C₃, C₁-C₄,C₁-C₆, more particularly C₁-C₄; in the case of “C₁-C₆-haloalkyl” or“C₁-C₆-haloalkoxy” even more particularly C₁-C₂.

Similarly, as used herein, the term “C₂-C₆”, as used throughout thistext, e.g. in the context of the definitions of “C₂-C₆-alkyl”, and“C₂-C₆-alkenyl” is to be understood as meaning an alkenyl group or analkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2,3, 4, 5, or 6 carbon atoms. It is to be understood further that saidterm “C₂-C₆” is to be interpreted as any sub-range comprised therein,e.g. C₂-C₆, C₃-C₅, C₃-C₄, C₂-C₃, C₂-C₄, C2-C₅, particularly C₂-C₃.

Further, as used herein, the term “C₃-C₆”, as used throughout this text,e.g. in the context of the definition of “C₃-C₆-cycloalkyl”, is to beunderstood as meaning a cycloalkyl group having a finite number ofcarbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to beunderstood further that said term “C₃-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₃-C₆, C₄-C₅, C₃-C₅, C₃-C₄, C₄-C₆,C₅-C₆; particularly C₃-C₆.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Should a substituent be composed of more than one part, as in case ofe.g. (C₁-C₄-alkoxy)-(C₁-C₄-alkyl)-, a hyphen at the beginning or at theend of the substituent marks the point of attachment to the rest of themolecule.

Ring system substituent means a substituent attached to an aromatic ornonaromatic ring system which, for example, replaces an availablehydrogen on the ring system.

As used herein, the term “one or more”, e.g. in the definition of thesubstituents of the compounds of the general formulae of the presentinvention, is understood as meaning “one, two, three, four or five,particularly one, two, three or four, more particularly one, two orthree, even more particularly one or two”.

As used herein, the term “leaving group” refers to an atom or a group ofatoms that is displaced in a chemical reaction as stable species takingwith it the bonding electrons. Preferably, a leaving group is selectedfrom the group comprising: halo, in particular chloro, bromo or iodo,methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy,nonafluorobutanesulfonyloxy, (4-bromo-benzene)sulfonyloxy,(4-nitro-benzene)sulfonyloxy, (2-nitro-benzene)-sulfonyloxy,(4-isopropyl-benzene)sulfonyloxy,(2,4,6-tri-isopropyl-benzene)-sulfonyloxy,(2,4,6-trimethyl-benzene)sulfonyloxy, (4-tertbutyl-benzene)sulfonyloxy,benzenesulfonyloxy, and (4-methoxy-benzene)sulfonyloxy.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S,³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I, respectively. Certainisotopic variations of a compound of the invention, for example, thosein which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence is preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of this invention optionally contain one or moreasymmetric centre, depending upon the location and nature of the varioussubstituents desired.

Asymmetric carbon atoms is present in the (R) or (S) configuration,resulting in racemic mixtures in the case of a single asymmetric centre,and diastereomeric mixtures in the case of multiple asymmetric centres.In certain instances, asymmetry may also be present due to restrictedrotation about a given bond, for example, the central bond adjoining twosubstituted aromatic rings of the specified compounds. The compounds ofthe present invention optionally contain sulphur atoms which areasymmetric, such as an asymmetric sulfoxide, of structure:

for example, in which * indicates atoms to which the rest of themolecule can be bound.

Substituents on a ring may also be present in either cis or trans form.It is intended that all such configurations (including enantiomers anddiastereomers), are included within the scope of the present invention.

Preferred compounds are those which produce the more desirablebiological activity. Separated, pure or partially purified isomers andstereoisomers or racemic or diastereomeric mixtures of the compounds ofthis invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivatisation, optimally chosen to maximise the separationof the enantiomers. Suitable chiral HPLC columns are manufactured byDaicel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivatisation, are also useful. The optically active compounds of thisinvention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

In order to limit different types of isomers from each other referenceis made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, e.g. R- or S- isomers, or E- orZ-isomers, in any ratio. Isolation of a single stereoisomer, e.g. asingle enantiomer or a single diastereomer, of a compound of the presentinvention is achieved by any suitable state of the art method, such aschromatography, especially chiral chromatography, for example.

Further, the compounds of the present invention may exist as tautomers.For example, any compound of the present invention which contains apyrazole moiety as a heteroaryl group for example can exist as a 1Htautomer, or a 2H tautomer, or even a mixture in any amount of the twotautomers, or a triazole moiety for example can exist as a 1H tautomer,a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said1H, 2H and 4H tautomers. Another example concerns dihydroxyoxazoleswhich can exist as tautomers as well, two of which are shown below:

The present invention includes all possible tautomers of the compoundsof the present invention as single tautomers, or as any mixture of saidtautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, andco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example asstructural element of the crystal lattice of the compounds. The amountof polar solvents, in particular water, may exist in a stoichiometric ornon-stoichiometric ratio. In the case of stoichiometric solvates, e.g. ahydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc.solvates or hydrates, respectively, are possible. The present inventionincludes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt. Said salt may be any salt, either an organic orinorganic addition salt, particularly any pharmaceutically acceptableorganic or inorganic addition salt, customarily used in pharmacy.

The term “pharmaceutically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention. For example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19. A suitable pharmaceuticallyacceptable salt of the compounds of the present invention may be, forexample, an acid-addition salt of a compound of the present inventionbearing a nitrogen atom, in a chain or in a ring, for example, which issufficiently basic, such as an acid-addition salt with an inorganicacid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric,bisulfuric, phosphoric, or nitric acid, for example, or with an organicacid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic,propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic,salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic,2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically acceptablecation, for example a salt with N-methyl-glucamine, dimethyl-glucamine,ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine,ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base,1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groupsmay be quaternised with such agents as lower alkyl halides such asmethyl, ethyl, propyl, and butyl chlorides, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

Those skilled in the art will further recognise that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

In the present text, in particular in the Experimental Section, for thesynthesis of intermediates and of examples of the present invention,when a compound is mentioned as a salt form with the corresponding baseor acid, the exact stoichiometric composition of said salt form, asobtained by the respective preparation and/or purification process, is,in most cases, unknown.

Unless specified otherwise, suffixes to chemical names or structuralformulae such as “hydrochloride”, “trifluoroacetate”, “sodium salt”, or“x HCl”, “x CF₃COOH”, “x Na⁺”, for example, are to be understood as nota stoichiometric specification, but solely as a salt form.

This applies analogously to cases in which synthesis intermediates orexample compounds or salts thereof have been obtained, by thepreparation and/or purification processes described, as solvates, suchas hydrates with (if defined) unknown stoichiometric composition.

As used herein, the term “in vivo hydrolysable ester” is understood asmeaning an in vivo hydrolysable ester of a compound of the presentinvention containing a carboxy or hydroxy group, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include for examplealkyl, cycloalkyl and optionally substituted phenylalkyl, in particularbenzyl esters, C₁-C₆ alkoxymethyl esters, e.g. methoxymethyl, C₁-C₆alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters,C₃-C₈ cycloalkoxy-carbonyloxy-C₁-C₆ alkyl esters, e.g.1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g.5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₆-alkoxycarbonyloxyethylesters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxygroup in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the present inventioncontaining a hydroxy group includes inorganic esters such as phosphateesters and [alpha]-acyloxyalkyl ethers and related compounds which as aresult of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy include alkanoyl,benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. The present invention covers allsuch esters.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorph, or as a mixture of more than one polymorph, in anyratio.

The present invention covers compounds of general formula (I), supra, inwhich R¹ represents a halogen atom or group selected from: C₁-C₆-alkyl,C₁-C₆-alkoxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, cyano,(C₁-C₆-alkyl)-S—, and (C₁-C₆-haloalkyl)-S—.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R¹ represents a group selectedfrom: C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,(C₁-C₆-alkyl)-S—, and (C₁-C₆-haloalkyl)-S—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, and(C₁-C₆-haloalkyl)-S—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkyl,C₁-C₃-haloalkoxy, (C₁-C₃-alkyl)-S—, and (C₁-C₃-haloalkyl)-S—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, and(C₁-C₃-haloalkyl)-S—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: ethyl, ethoxy, cyano, —CF₃, —OCF₃, —SCF₃, iso-propyl,iso-propoxy, and —OCHF₂.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: ethyl, ethoxy-, —OCF₃, iso-propyl, iso-propoxy, and—OCHF₂.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: —OCF₃, and —OCHF₂.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: ethyl, ethoxy, iso-propyl, and iso-propoxy.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: —OCF₃, —SCF₃, and —CF₃.

The present invention covers compounds of general formula (I), supra, inwhich R⁵ represents a phenyl or heteroaryl group; wherein said group isoptionally substituted, with one or more substituents, which areindependently of each other selected from: halo-, cyano, C₁-C₆-alkyl,C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, nitro, R¹³O—,R¹³S—, R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,R¹³OC(═O)—(C₁-C₆-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-,R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-,(C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂—,(C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³, —C(═O)N(R¹⁴)R¹⁵,—C(═O)N(R¹⁴)S(═O)₂R¹⁶, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶, —N(R¹⁴)C(═O)R¹⁷,—N(R¹⁴)S(═O)₂R¹⁶, —S(═O)₂OR¹³, and —S(═O)₂N(R¹⁴)R¹⁵.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R⁵ represents a phenyl orheteroaryl group; wherein said group is optionally substituted, with oneor more substituents, which are independently of each other selectedfrom: halo-, cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,R¹³O—, R¹³S—, (C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—,(C₁-C₆-alkyl)-S(═O)₂—, (C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a phenylor heteroaryl group; wherein said group is optionally substituted, withone or more substituents, which are independently of each other selectedfrom: halo-, cyano, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy,R¹³O—, R¹³S—, (C₁-C₃-alkyl)-S—, (C₁-C₃-alkyl)-S(═O)—,(C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a phenylor heteroaryl group; wherein said group is optionally substituted, withone or more substituents, which are independently of each other selectedfrom: halo-, C₁-C₃-alkyl, C₁-C₃-haloalkyl, R¹³O—, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a phenylor heteroaryl group; wherein said group is optionally substituted, withone, two or three substituents, which are independently of each otherselected from: halo-, C₁-C₃-alkyl, C₁-C₃-haloalkyl, R¹³O—, —C(═O)OR¹³,and —C(═O)N(R¹⁴)R¹⁵.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents anphenyl or heteroaryl group; wherein said group is optionallysubstituted, with one or more substituents, which are independently ofeach other selected from: halo-, cyano-, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, nitro, R¹³O—, R¹³S—,R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl),R¹³OC(═O)—(C₁-C₆-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-,R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-,(C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂—,(C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³, —C(═O)N(R¹⁴)R¹⁵,—C(═O)N(R¹⁴)S(═O)₂R¹⁶, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶, —N(R¹⁴)C(═O)R¹⁷,—N(R¹⁴)S(═O)₂R¹⁶, —S(═O)₂OR¹³, and —S(═O)₂N(R¹⁴)R¹⁵; wherein saidheteroaryl group is selected from: thienyl, furanyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, tetrazolyl, thiadiazolyl, thia-4H-pyrazolyl, benzofuranyl,benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl,benzotriazolyl, indazolyl, indolyl, isoindolyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, quinazolinyl,isoquinolinyl, azocinyl, indolizinyl, purinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, andoxepinyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a phenylor heteroaryl group; wherein said group is optionally substituted, withone or more substituents, which are independently of each other selectedfrom: halo-, cyano, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl,C₁-C₆-haloalkoxy, nitro, R¹³O—, R¹³S—, R¹³OC(═O)—(C₁-C₆-alkyl)-,R¹³OC(═O)—(C₂-C₆-alkenyl), R¹³OC(═O)—(C₁-C₆-alkoxy)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-, R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-, (C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—,(C₁-C₆-alkyl)-S(═O)₂—, (C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³,—C(═O)N(R¹⁴)R¹⁵, —C(═O)N(R¹⁴)S(═O)₂R¹⁶, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶,—N(R¹⁴)C(═O)R¹⁷, —N(R¹⁴)S(═O)₂R¹⁶, —S(═O)₂OR¹³, and —S(═O)₂N(R¹⁴)R¹⁵;wherein said heteroaryl group is selected from: thienyl, furanyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,thia-4H-pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, andtriazinyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a phenylor heteroaryl group; wherein said group is optionally substituted, withone or more substituents, which are independently of each other selectedfrom: halo-, cyano, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl,C₁-C₆-haloalkoxy, nitro, R¹³O—, R¹³S—, R¹³OC(═O)—(C₁-C₆-alkyl)-,R¹³OC(═O)—(C₂-C₆-alkenyl)-, R¹³OC(═O)—(C₁-C₆-alkoxy)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-, R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-, (C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—,(C₁-C₆-alkyl)-S(═O)₂—, (C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³,—C(═O)N(R¹⁴)R¹⁵, —C(═O)N(R¹⁴)S(═O)₂R¹⁶, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶,—N(R¹⁴)C(═O)R¹⁷, —N(R¹⁴)S(═O)₂R¹⁶, —S(═O)₂OR¹³, and —S(═O)₂N(R¹⁴)R¹⁵;wherein said heteroaryl group is selected from: oxazolyl, pyrazolyl,oxadiazolyl, triazolyl, tetrazolyl, and pyridinyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a phenylor heteroaryl group; wherein said group is optionally substituted, withone or more substituents, which are independently of each other selectedfrom: halo-, cyano, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl,C₁-C₆-haloalkoxy, nitro, R¹³O—, R¹³S—, R¹³OC(═O)—(C₁-C₆-alkyl)-,R¹³OC(═O)—(C₂-C₆-alkenyl)-, R¹³OC(═O)—(C₁-C₆-alkoxy)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-, R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-, (C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—,(C₁-C₆-alkyl)-S(═O)₂—, (C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³,—C(═O)N(R¹⁴)R¹⁵, —C(═O)N(R¹⁴)S(═O)₂R¹⁶, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶,—N(R¹⁴)C(═O)R¹⁷, —N(R¹⁴)S(═O)₂R¹⁶, —S(═O)₂OR¹³, and —S(═O)₂N(R¹⁴)R¹⁵;wherein said heteroaryl group is selected from: 1,2-oxazol-4-yl,1,3-oxazol-5-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, pyridin-4-yl,1,3,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1H-tetrazol-5-yl, 1,2,4-triazol-3-yl, and 1,3,4-oxadiazol-2-yl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a phenylor heteroaryl group; wherein said group is optionally substituted, withone or more substituents, which are independently of each other selectedfrom: halo-, C₁-C₆-alkyl, C₁-C₆-haloalkyl, R¹³O—, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵; wherein said heteroaryl group is selected from:thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, thia-4H-pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, and triazinyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a phenylor heteroaryl group; wherein said group is optionally substituted, withone, two or three substituents, which are independently of each otherselected from: halo-, C₁-C₃-alkyl, C₁-C₃-haloalkyl, R¹³O—, —C(═O)OR¹³,and —C(═O)N(R¹⁴)R¹⁵; wherein said heteroaryl group is selected from:thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,thiadiazolyl, thia-4H-pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, and triazinyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a phenylor heteroaryl group; wherein said group is optionally substituted, withone or more substituents, which are independently of each other selectedfrom: halo-, C₁-C₆-alkyl, C₁-C₆-haloalkyl, R¹³O—, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵; wherein said heteroaryl group is selected from:oxazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, and pyridinyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a phenylor heteroaryl group; wherein said group is optionally substituted, withone or more substituents, which are independently of each other selectedfrom: halo-, C₁-C₃-alkyl, C₁-C₃-haloalkyl, R¹³O—, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵; wherein said heteroaryl group is selected from:oxazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, and pyridinyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a phenylor heteroaryl group; wherein said group is optionally substituted, withone, two or three substituents, which are independently of each otherselected from: fluoro, methyl, methoxy, ethoxy, hydroxy, —CF₃, —C(═O)OH,—C(═O)OCH₃, and —C(═O)NH₂; wherein said heteroaryl group is selectedfrom: oxazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, andpyridinyl.

The present invention covers compounds of general formula (I), supra, inwhich R⁶ represents a hydrogen atom or a halogen atom or group selectedfrom: C₁-C₆-alkyl, and C₁-C₆-alkoxy.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R⁶ represents a hydrogen atom or ahalogen atom or group selected from: C₁-C₃-alkyl, and C₁-C₃-alkoxy.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R⁶ represents a hydrogen atom or aC₁-C₃-alkyl group.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R⁶ represents a hydrogen atom or amethyl group.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R⁶ represents a hydrogen atomgroup.

The present invention covers compounds of general formula (I), supra, inwhich R⁸ represents a C₁-C₃-alkyl group.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R⁸ represents a C₁-C₂-alkyl group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁸ represents a methylgroup.

The present invention covers compounds of general formula (I), supra, inwhich R⁹, R¹⁰, and R¹¹ are independently of each other selected from:hydrogen and C₁-C₃-alkyl.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R⁹, R¹⁰, and R¹¹ are independentlyof each other selected from: hydrogen and methyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁸ represents ahydrogen atom, R⁹ represents a hydrogen atom, R¹⁰ represents a methylgroup, and R¹¹ represents a methyl group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁸ represents a methylgroup, R⁹ represents a hydrogen atom, R¹⁰ represents a methyl group, andR¹¹ represents a methyl group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁸ represents a methylgroup, R⁹ represents a methyl group, R¹⁰ represents a methyl group, andR¹¹ represents a methyl group.

The present invention covers compounds of general formula (I), supra, inwhich R¹³ represents a hydrogen atom or a group selected from:C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-, and(C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-.

The present invention covers compounds of general formula (I), supra, inwhich R¹³ represents a hydrogen atom or a group selected from:C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-, and(C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R¹³ represents a hydrogen atom or aC₁-C₃-alkyl group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹³ represents ahydrogen atom or a methyl group.

The present invention covers compounds of general formula (I), supra, inwhich R¹⁴ and R¹⁵ are independently of each other selected from:hydrogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-,(C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-, C₁-C₆-haloalkyl, H₂N-(C₂-C₆-alkyl)-,(C₁-C₃-alkyl)N(H)(C₂-C₆-alkyl)-, (C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-,R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to 6-membered heterocycloalkyl, phenyl,heteroaryl, phenyl-(C₁-C₆-alkyl)-, and heteroaryl-(C₁-C₆-alkyl)-;wherein phenyl and heteroaryl groups are optionally substituted with oneor two substituents, which are independently of each other selectedfrom: C₁-C₃-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and—C(═O)NH₂; or R¹⁴ and R¹⁵ together with the nitrogen atom to which theyare attached form a 4-6-membered heterocycloalkyl; said 4-6-memberedheterocycloalkyl being optionally substituted with one substituentselected from: C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy,C₁-C₃-haloalkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy,halogen, and cyano; or said 4-6-membered heterocycloalkyl beingoptionally substituted with one or two halogen atoms.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R¹⁴ and R¹⁵ are independently ofeach other selected from: hydrogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,HO—(C₂-C₆-alkyl)-, (C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-, C₁-C₆-haloalkyl,H₂N-(C₂-C₆-alkyl)-, (C₁-C₃-alkyl)N(H)(C₂-C₆-alkyl)-,(C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-, R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to6-membered heterocycloalkyl, phenyl, heteroaryl, phenyl-(C₁-C₆-alkyl)-,and heteroaryl-(C₁-C₆-alkyl)-; wherein phenyl and heteroaryl groups areoptionally substituted with one or two substituents, which areindependently of each other selected from: C₁-C₃-alkyl,C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and —C(═O)NH₂.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ and R¹⁵ areindependently of each other selected from: hydrogen, C₁-C₆-alkyl, andC₃-C₆-cycloalkyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ and R¹⁵ areindependently of each other selected from: hydrogen, and C₁-C₃-alkyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ represents ahydrogen atom and R¹⁵ represents a hydrogen atom.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ and R¹⁵ togetherwith the nitrogen atom to which they are attached form a 4-6-memberedheterocycloalkyl; said 4-6-membered heterocycloalkyl being optionallysubstituted with one substituent selected from: C₁-C₃-alkyl,C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyloxy, amino, hydroxy, halogen, and cyano; or said4-6-membered heterocycloalkyl being optionally substituted with one ortwo halogen atoms.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ and R¹⁵ togetherwith the nitrogen atom to which they are attached form a 4-6-memberedheterocycloalkyl; said 4-6-membered heterocycloalkyl being optionallysubstituted with one substituent selected from: C₁-C₃-alkyl,C₁-C₃-haloalkyl; or said 4-6-membered heterocycloalkyl being optionallysubstituted with one or two halogen atoms.

The present invention covers compounds of general formula (I), supra, inwhich R¹⁶ represents a hydrogen atom or a group selected from:C₁-C₆-alkyl, HO—(C₁-C₆-alkyl)-, C₃-C₆-cycloalkyl,HO—(C₃-C₆-cycloalkyl)-, C₁-C₆-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-,phenyl, heteroaryl, and 4- to 6-membered heterocycloalkyl;wherein phenyland heteroaryl groups are optionally substituted with one or twosubstituents, which are independently of each other selected from:C₁-C₃-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R¹⁶ represents a hydrogen atom or agroup selected from: C₁-C₃-alkyl, HO—(C₁-C₃-alkyl)-, C₃-C₆-cycloalkyl,HO—(C₃-C₆-cycloalkyl)-, C₁-C₃-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-,phenyl, heteroaryl, and 4- to 6-membered heterocycloalkyl; whereinphenyl and heteroaryl groups are optionally substituted with one or twosubstituents, which are independently of each other selected from:C₁-C₃-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁶ represents ahydrogen atom or a group selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,HO—(C₃-C₆-cycloalkyl)-, C₁-C₃-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-,phenyl, and 4- to 6-membered heterocycloalkyl; wherein the phenyl groupis optionally substituted with one or two substituents, which areindependently of each other selected from: C₁-C₃-alkyl,C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and —C(═O)N(R¹⁴)R¹⁵.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁶ represents ahydrogen atom or a group selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,HO—(C₃-C₆-cycloalkyl)-, C₁-C₃-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-,phenyl, and 4- to 6-membered heterocycloalkyl; wherein the phenyl groupis optionally substituted with one or two halogen atoms.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁶ represents ahydrogen atom or a group selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,(C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, and phenyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁶ represents ahydrogen atom.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁶ represents a groupselected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl, and(C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-.

The present invention covers compounds of general formula (I), supra, inwhich R¹⁷ represents a group selected from: —N(R¹⁴)R¹⁵ and C₁-C₆-alkoxy.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R¹⁷ represents a —N(R¹⁴)R¹⁵ group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁷ represents aC₁-C₃-alkoxy- group.

In another preferred embodiment, the present invention relates tocompounds of general formula (Ia)

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R¹² are as defined for thecompounds of general formula (I) in any of the above mentionedembodiments.

In another preferred embodiment, the present invention relates tocompounds of general formula (Ib)

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R¹² are as defined for thecompounds of general formula (I) in any of the above mentionedembodiments.

In another preferred embodiment, the present invention relates tocompounds of general formula (Ic)

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R¹² are as defined for thecompounds of general formula (I) in any of the above mentionedembodiments.

In another preferred embodiment, the present invention relates tocompounds of general formula (Id)

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R¹² are as defined for thecompounds of general formula (I) in any of the above mentionedembodiments.

It is to be understood that the present invention relates also to anycombination of the preferred embodiments described above.

Some examples of combinations are given hereinafter. However, theinvention is not limited to these combinations.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I):

in which:

-   R¹ represents a halogen atom or group selected from:    -   C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,        cyano, (C₁-C₆-alkyl)-S—, and (C₁-C₆-haloalkyl)-S—;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a phenyl or heteroaryl group; wherein said group is    optionally substituted, with one or more substituents, which are    independently of each other selected from:    -   halo-, cyano, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl,        C₁-C₆-haloalkoxy, nitro, R¹³O—, R¹³S—, R¹³OC(═O)—(C₁-C₆-alkyl)-,        R¹³OC(═O)—(C₂-C₆-alkenyl)-, R¹³OC(═O)—(C₁-C₆-alkoxy)-,        R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-, R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-, (C₁-C₆-alkyl)-S—,        (C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂—,        (C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³, —C(═O)N(R¹⁴)R¹⁵,        —C(═O)N(R¹⁴)S(═O)₂R¹⁶, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶,        —N(R¹⁴)C(═O)R¹⁷, —N(R¹⁴)S(═O)₂R¹⁶, —S(═O)₂OR¹³, and        —S(═O)₂N(R¹⁴)R¹⁵;    -   wherein said heteroaryl group is selected from: thienyl,        furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,        isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,        thiadiazolyl, thia-4H-pyrazolyl, pyridinyl, pyridazinyl,        pyrimidinyl, pyrazinyl, and triazinyl;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from:    -   C₁-C₆-alkyl, and C₁-C₆-alkoxy;-   R⁷ represents a hydrogen atom;-   R⁸ represents a C₁-C₃-alkyl group;-   R⁹, R¹⁰, and R¹¹    -   are independently of each other selected from: hydrogen and        C₁-C₃-alkyl;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a group selected from:    C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-, and    (C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₆-alkyl, and C₃-C₆-cycloalkyl;-   or-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl; said 4-6-membered        heterocycloalkyl being optionally substituted with one        substituent selected from: C₁-C₃-alkyl, C₁-C₃-haloalkyl; or said        4-6-membered heterocycloalkyl being optionally substituted with        one or two halogen atoms;-   R¹⁶ represents a hydrogen atom or a group selected from:    C₁-C₃-alkyl, C₃-C₆-cycloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, and    phenyl;-   R¹⁷ represents a group selected from: —N(R¹⁴)R¹⁵ and C₁-C₃-alkoxy;-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a halogen atom or group selected from:    -   C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,        and (C₁-C₆-haloalkyl)-S—;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a phenyl or heteroaryl group; wherein said group is    optionally substituted, with one or more substituents, which are    independently of each other selected from:    -   halo-, cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,        R¹³O—, R¹³S—, (C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—,        (C₁-C₆-alkyl)-S(═O)₂—, (C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³, and        —C(═O)N(R¹⁴)R¹⁵;    -   wherein said heteroaryl group is selected from: thienyl,        furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,        isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl,        thiadiazolyl, thia-4H-pyrazolyl, pyridinyl, pyridazinyl,        pyrimidinyl, pyrazinyl, and triazinyl;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from:    -   C₁-C₆-alkyl, and C₁-C₆-alkoxy;-   R⁷ represents a hydrogen atom;-   R⁸ represents a C₁-C₃-alkyl group;-   R⁹, R¹⁰, and R¹¹    -   are independently of each other selected from: hydrogen and        C₁-C₃-alkyl;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₃-alkyl group;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen, and        C₁-C₃-alkyl;-   or-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl; said 4-6-membered        heterocycloalkyl being optionally substituted with one        substituent selected from: C₁-C₃-alkyl, and C₁-C₃-haloalkyl;-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a halogen atom or group selected from:    -   C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, and (C₁-C₆-haloalkyl)-S—;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a phenyl or heteroaryl group; wherein said group is    optionally substituted, with one or more substituents, which are    independently of each other selected from:    -   halo-, cyano, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,        R¹³O—, R¹³S—, —C(═O)OR¹³, and —C(═O)N(R¹⁴)R¹⁵;    -   wherein said heteroaryl group is selected from: oxazolyl,        pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, and pyridinyl;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from:    -   C₁-C₆-alkyl, and C₁-C₆-alkoxy;-   R⁷ represents a hydrogen atom;-   R⁸ represents a C₁-C₃-alkyl group;-   R⁹, R¹⁰, and R¹¹    -   are independently of each other selected from: hydrogen and        C₁-C₃-alkyl;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₃-alkyl group;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen, and        C₁-C₃-alkyl;-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a halogen atom or group selected from:    -   C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, and (C₁-C₆-haloalkyl)-S—;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a phenyl or heteroaryl group; wherein said group is    optionally substituted, with one or more substituents, which are    independently of each other selected from:    -   halo-, C₁-C₆-alkyl, C₁-C₆-haloalkyl, R¹³O—, —C(═O)OR¹³, and        —C(═O)N(R¹⁴)R¹⁵;    -   wherein said heteroaryl group is selected from: oxazolyl,        pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, and pyridinyl;-   R⁶ represents a hydrogen atom or a C₁-C₃-group;-   R⁷ represents a hydrogen atom;-   R⁸ represents a C₁-C₃-alkyl group;-   R⁹, R¹⁰, and R¹¹    -   are independently of each other selected from: hydrogen and        C₁-C₃-alkyl;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₃-alkyl group;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen, and        C₁-C₃-alkyl;-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a C₁-C₃-haloalkoxy group;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a phenyl or heteroaryl group;    -   wherein said phenyl group is substituted with one substituent        selected from: —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂;    -   wherein said heteroaryl group is selected from:        3,5-dimethyl-1,2-oxazol-4-yl, 1H-pyrazol-4-yl,        3,5-dimethyl-1H-pyrazol-4-yl, 3-methyl-1H-pyrazol-4-yl,        1H-pyrazol-5-yl, 1,2-oxazol-4-yl, 1,3-dimethyl-1H-pyrazol-5-yl,        1-methyl-1H-pyrazol-4-yl, 2-methoxypyridin-4-yl,        1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl,        5-methyl-1,3,4-oxadiazol-2-yl, 1H-tetrazol-5-yl,        5-methyl-4H-1,2,4-triazol-3-yl,        3-ethoxy-5-methyl-1,2-oxazol-4-yl;-   R⁶ represents a hydrogen atom or a methyl group;-   R⁷ represents a hydrogen atom;-   R⁸ represents a C₁-C₃-alkyl group;-   R⁹ represents a hydrogen atom or a C₁-C₃-alkyl group;-   R¹⁰ represents a C₁-C₃-alkyl group;-   R¹¹ represents a C₁-C₃-alkyl group;-   R¹² represents a hydrogen atom;-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

In accordance with a first aspect, the present invention coverscompounds of general formula (I):

in which:

-   R¹ represents —O—CF₃;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a phenyl or heteroaryl group;    -   wherein said phenyl group is optionally substituted, with one        substituent selected from: —C(═O)OH, —C(═O)OCH₃, —C(═O)NH₂,        wherein said heteroaryl group is selected from:        3,5-dimethyl-1,2-oxazol-4-yl, 1H-pyrazol-4-yl,        3,5-dimethyl-1H-pyrazol-4-yl, 3-methyl-1H-pyrazol-4-yl,        1H-pyrazol-5-yl, 1,2-oxazol-4-yl, 1,3-dimethyl-1H-pyrazol-5-yl,        1-methyl-1H-pyrazol-4-yl, 2-methoxypyridin-4-yl,        1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl,        5-methyl-1,3,4-oxadiazol-2-yl, 1H-tetrazol-5-yl,        5-methyl-4H-1,2,4-triazol-3-yl,        3-ethoxy-5-methyl-1,2-oxazol-4-yl;-   R⁶ represents a hydrogen atom or a methyl group;-   R⁷ represents a hydrogen atom;-   R⁸ represents a methyl group;-   R⁹ represents a hydrogen atom or a methyl group;-   R¹⁰ represents a methyl group;-   R¹¹ represents a methyl group;-   R¹² represents a hydrogen atom;-   or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or    a salt thereof, or a mixture of same.

It is to be understood that the present invention relates to anysub-combination within any embodiment or aspect of the present inventionof compounds of general formula (I), supra.

More particularly still, the present invention covers compounds ofgeneral formula (I) which are disclosed in the Example section of thistext, infra.

In accordance with another aspect, the present invention covers methodsof preparing compounds of the present invention, said methods comprisingthe steps as described in the Experimental Section herein.

In accordance with an embodiment, the present invention also relates toa method of preparing a compound of general formula (I) as definedsupra, said method comprising the step of allowing an intermediatecompound of general formula (VI):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) supra,

to react with a compound of general formula (III):

in which R¹, R² and R³ are as defined as for the compound of generalformula (I), supra,

thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are asdefined for the compound of general formula (I) supra.

In accordance with another embodiment, the present invention alsorelates to a method of preparing a compound of general formula (I) asdefined supra, said method comprising the step of allowing anintermediate compound of general formula (IV):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) supra,

to react with a compound of general formula (V):

in which R¹, R², R³ and R¹² are as defined as for the compound ofgeneral formula (I), supra,

thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are asdefined for the compound of general formula (I) supra.

In accordance with another embodiment, the present invention alsorelates to a method of preparing a compound of general formula (I) asdefined supra, said method comprising the step of allowing anintermediate compound of general formula (II):

in which R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined for thecompound of general formula (I) supra, and LG is a leaving group,preferably a halogen atom, more preferably a bromine atom,

to react with a compound of general formula (VII):

R⁵—Y   (VII)

in which R⁵ is as defined as for the compound of general formula (I),supra, and Y is a group enabling palladium catalysed coupling reactions,including a boronic acid group, an ester of a boronic acid group, a MIDAboronate, and a potassium fluoro borate;

thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are asdefined for the compound of general formula (I) supra.

In a preferred embodiment, R⁵—Y is selected from:

wherein R^(B1) and R^(B2) represent, independently from each other, ahydrogen atom or a C₁-C₆-alkyl- or C₃-C₆-cycloalkyl- group;

or

R^(B1) and R^(B2) together represent a C₂-C₆-alkylene group.

In another preferred embodiment, R⁵—Y represents anN-methyliminodiacetic acid (MIDA) boronate:

In another preferred embodiment, R⁵—Y represents

In accordance with a further aspect, the present invention coversintermediate compounds which are useful for the preparation of thecompounds of general formula (I), supra.

Particularly, the inventions covers intermediate compounds of generalformula (II):

in which R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined for thecompound of general formula (I) supra, and LG is a leaving group,preferably a halogen atom, more preferably a bromine atom,

intermediate compounds of general formula (VI):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) supra,

and

intermediate compounds of general formula (IV):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) supra.

More particularly still, the present invention covers the intermediatecompounds which are disclosed in the Example section of this text,infra.

In accordance with a further aspect, the present invention covers theuse of the intermediate compounds of general formula (VI):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) supra, for the preparation of a compoundof general formula (I) as defined supra.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula (IV):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) supra, for the preparation of a compoundof general formula (I) as defined supra.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula (II):

in which R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined for thecompound of general formula (I) supra, and LG is a leaving group,preferably a halogen atom, more preferably a bromine atom,

for the preparation of a compound of general formula (I) as definedsupra.

In accordance with a further aspect, the present invention relates tocompounds of general formula (I), as decribed supra, or a stereoisomer,a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof,particularly a pharmaceutically acceptable salt thereof, or a mixture ofsame, for use in the treatment or prophylaxis of a disease.

In accordance with a further aspect, the present invention relates to apharmaceutical composition comprising a compound of general formula (I),as decribed supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate,a solvate, or a salt thereof, particularly a pharmaceutically acceptablesalt thereof, or a mixture of same, and a pharmaceutically acceptablediluent or carrier.

Particularly, the pharmaceutical combination comprises:

-   -   one or more first active ingredients selected from a compound of        general formula (I) as decribed supra, and    -   one or more second active ingredients selected from        chemotherapeutic anti-cancer agents (see below).

In accordance with a further aspect, the present invention relates touse of a compound of general formula (I), as described supra, or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, particularly a pharmaceutically acceptable salt thereof, or amixture of same, for the prophylaxis or treatment of a disease.

In accordance with a further aspect, the present invention relates touse of a compound of general formula (I), as described supra, or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, particularly a pharmaceutically acceptable salt thereof, or amixture of same, for the preparation of a medicament for the prophylaxisor treatment of a disease.

The disease as mentioned before is in particular a disease ofuncontrolled cell growth, proliferation and/or survival, aninappropriate cellular immune response, or an inappropriate cellularinflammatory response, particularly in which the disease of uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune response, or inappropriate cellular inflammatory response is ahaematological tumour, a solid tumour and/or metastases thereof, e.g.leukaemias and myelodysplastic syndrome, malignant lymphomas, head andneck tumours including brain tumours and brain metastases, tumours ofthe thorax including non-small cell and small cell lung tumours,gastrointestinal tumours, endocrine tumours, mammary and othergynaecological tumours, urological tumours including renal, bladder andprostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

Experimental Section

The following table lists the abbreviations used in this paragraph andin the Intermediate Examples and Examples section as far as they are notexplained within the text body. NMR peak forms are stated as they appearin the spectra, possible higher order effects have not been considered.Chemical names were generated using the ICS naming tool of ACD labs. Insome cases generally accepted names of commercially available reagentswere used in place of ICS naming tool generated names.

Abbreviation Meaning ACN acetonitrile br. broad signal in NMR br. s.broad singlet CDI di-1H-imidazol-1-ylmethanone CD₃OD deuterated methanolDMF N,N-dimethylformamide d doublet dd doublet of doublets ddd doubletof doublet of doublets DMSO dimethyl sulfoxide dquint doublet ofquintets EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride ESI electrospray ionization EtOH ethanol h hour(s) HATUN-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HClhydrochloric acid HCOOH formic acid HOBt hydroxybenzotriazole HPLC, LChigh performance liquid chromatography LiOH lithium hydroxide mmultiplet m_(c) centered multiplet min minute(s) MS mass spectroscopyMeOH methanol NaOH sodium hydroxide Na₂CO₃ sodium carbonate Na₂SO₄sodium sulfate NEt₃ triethylamine NH₄Cl ammonium chloride NMPN-methyl-2-pyrrolidone NMR nuclear magnetic resonance Pd₂(dba)₃tris(dibenzylideneacetone)dipalladium PyBOP(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphatequint quintet qt quartet of triplets R_(t) retention time rt roomtemperature s singlet t triplet tt triplet of triplets T3Ppropylphosphonic anhydride, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide solution, PPACA, T3P ®. THFtetrahydrofurane UPLC ultra performance liquid chromatography Xanthphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Other abbreviations have their meanings customary per se to the skilledperson. The various aspects of the invention described in thisapplication are illustrated by the following examples which are notmeant to limit the invention in any way.

Syntheses of Compounds (Overview)

The following schemes and general procedures illustrate generalsynthetic routes to the compounds of general formula (I) of theinvention and are not intended to be limiting. It is obvious to theperson skilled in the art that the order of transformations asexemplified in Schemes 1 to 3 can be modified in various ways. The orderof transformations exemplified in Schemes 1 to 3 is therefore notintended to be limiting. In addition, interconversion of substituents,for example of residues R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ can be achievedbefore and/or after the exemplified transformations. These modificationscan be such as the introduction of protecting groups, cleavage ofprotecting groups, reduction or oxidation of functional groups,halogenation, metallation, substitution or other reactions known to theperson skilled in the art. These transformations include those whichintroduce a functionality which allows for further interconversion ofsubstituents. Appropriate protecting groups and their introduction andcleavage are well-known to the person skilled in the art (see forexample T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3rd edition, Wiley 1999).

in which R¹, R², R3, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are asdefined supra, LG represents a leaving group such as a halogen atom, Xrepresents a halogen atom, and Y represents boronic acid or a boronicester or a trifluoroborate such as potassium fluoro borate.

Suitably functionalized compounds of formula (II) may be reacted withboronic acids or the corresponding pinacol esters or the correspondingtrifluoroborates of general formula (VII) in a suitable solvent such asfor example dioxane and the help of Pd catalysts such as for exampleferrocen at temperatures between 0° C. and 70° C. Boronic acids or thecorresponding pinacol esters or the corresponding trifluoroborates (VII)are either commercially available, known compounds or may be formed fromknown compounds by known methods by a person skilled in the art.

Suitably functionalized diamines of formula 4 may be reacted withthioisocyanates of general formula 5 in a suitable solvent such as forexample tetrahydrofurane and in the presence of a carbodiimide such asfor example diisopropylcarbodiimide or EDC at temperatures between 0° C.and the boiling point of the solvent, typically at 70° C.Thioisocyanates 5 are either commercially available, known compounds ormay be formed from known compounds by known methods by a person skilledin the art.

Diamines of general formula 4 in turn may be obtained from nitroanilinesof general formula 3 by reduction. For reduction, all processes that areknown to the person skilled in the art may be applied. Nitroanilines 3may be hydrogenated under an atmosphere of hydrogen at pressures between1 bar and 100 bar in a suitable solvent such as for example ethylacetate, tetrahydrofurane, methanol or ethanol and in the presence of ametal catalyst such as for example palladium on charcoal at temperaturesbetween 0° C. and the boiling point of the solvent, typically at roomtemperature. The addition of a suitable acid such as for examplehydrochloric acid or acetic acid may be necessary. Alternatively,nitroanilines of general formula 3 may be reduced with iron/NH₄Cl ortin(II) chloride in a suitable solvent such as for example water,methanol or ethanol or mixtures thereof at temperatures between roomtemperature and the boiling point of the solvent, typically at 70° C.Nitroanilines of general formula 3 can be obtained from nitroarenes ofgeneral formula 1 by nucleophilic substitution with amines of generalformula 2 in a suitable solvent such as for example tetrahydrofurane andin the presence of a suitable base such as for example potassiumcarbonate or triethylamine at temperatures between room temperature andthe boiling point of the solvent, typically at 50-70° C. Instead ofusing amines of general formula 2 their corresponding ammonium salts canbe used as well. Nitroarenes 1 and amines 2 or their correspondingammonium salts are either commercially available, known compounds or maybe formed from known compounds by known methods by a person skilled inthe art.

in which R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and LG are as defined supra.

An alternative route to nitroanilines of general formula 3 via reductiveamination is outlined in Scheme 2. Nitroanilines 4 may be reacted withcyclohexanones 5 in a suitable solvent such as for exampledichloromethane or dichloroethane and in the presence of a reducingagent such as for example sodium borohydride or sodiumtriacetoxyborohydride at temperatures between 0° C. and the boilingpoint of the solvent, typically at room temperature. It might benecessary to add an acid such as for example trifluoroacetic acid to thereaction mixture. Nitroanilines 4 and cyclohexanones 5 are eithercommercially available, known compounds or may be formed from knowncompounds by known methods by a person skilled in the art.

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are asdefined supra.

Suitably functionalized chlorobenzimidazoles (IV) may be reacted withanilines of general formula (V) in a suitable solvent such as forexample NMP at temperatures between room temperature and the boilingpoint of the solvent, typically at 110° C. Anilines (V) are eithercommercially available, known compounds or may be formed from knowncompounds by known methods by a person skilled in the art.Chlorobenzimidazoles (IV) in turn can be obtained from benzimidazolonesof general formula 6 by reaction in chlorinating agents such as forexample phosphoric trichloride at temperatures between room temperatureand the boiling point of the reagent, typically at 105° C.Benzimidazolones of general formula 6 may be synthesized from suitablyfunctionalized diamines of general formula (VI) by reaction withcarbonic acid equivalents such as for example CDI, phosgene or phosgenederivatives in a suitable solvent such as for example DMF ortetrahydrofurane at temperatures between room temperature and theboiling point of the solvent, typically at 50° C.

General Part

All reagents, for which the synthesis is not described in theexperimental part, are either commercially available, or are knowncompounds or may be formed from known compounds by known methods by aperson skilled in the art.

The compounds and intermediates produced according to the methods of theinvention may require purification. Purification of organic compounds iswell known to the person skilled in the art and there may be severalways of purifying the same compound. In some cases, no purification maybe necessary. In some cases, the compounds may be purified bycrystallization. In some cases, impurities may be stirred out using asuitable solvent. In some cases, the compounds may be purified bychromatography, particularly flash column chromatography, using forexample prepacked silica gel cartridges, e.g. Biotage SNAP cartidgesKP-Sil® or KP-NH® in combination with a Biotage autopurifier system(SP4® or Isolera Four®) and eluents such as gradients of hexane/ethylacetate or DCM/methanol. In some cases, the compounds may be purified bypreparative HPLC using for example a Waters autopurifier equipped with adiode array detector and/or on-line electrospray ionization massspectrometer in combination with a suitable prepacked reverse phasecolumn and eluents such as gradients of water and acetonitrile which maycontain additives such as trifluoroacetic acid, formic acid or aqueousammonia.

In some cases, purification methods as described above can provide thosecompounds of the present invention which possess a sufficiently basic oracidic functionality in the form of a salt, such as, in the case of acompound of the present invention which is sufficiently basic, atrifluoroacetate or formate salt for example, or, in the case of acompound of the present invention which is sufficiently acidic, anammonium salt for example. A salt of this type can either be transformedinto its free base or free acid form, respectively, by various methodsknown to the persion skilled in the art, or be used as salts insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base etc.) of a compound of the present inventionas isolated and as described herein is not necessarily the only form inwhich said compound can be applied to a biological assay in order toquantify the specific biological activity.

UPLC-MS Standard Procedures

Analytical UPLC-MS was performed as described below. The masses (m/z)are reported from the positive mode electrospray ionisation unless thenegative mode is indicated (ES−).

In most of the cases method A is used. If not, it is indicated.

UPLC-MS Method A

Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEHC18 1.7 50×2.1 mm; Eluent A: water+0.1% formic acid, Eluent B:acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate0.8 mL/min; Temperature: 60° C.; Injection: 2 μL; DAD scan: 210-400 nm.

UPLC-MS Method B

Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEHC18 1.7 50×2.1 mm; Eluent A: water+0.2% ammonia, Eluent B: acetonitrile;Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL/min;Temperature: 60° C.; Injection: 2 μL; DAD scan: 210-400 nm; ELSD.

UPLC-MS Method C

Instrument: Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH C181.7 50×2.1 mm; Eluent A: water+0.05% formic acid, Eluent B:acetonitrile+0.05% formic acid; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min99% B; Flow rate 0.8 mL/min; Temperature: 60° C.; Injection: 2 μL; DADscan: 210-400 nm.

UPLC-MS Method D

Instrument: Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH C181.7 50×2.1 mm; Eluent A: water+0.2% ammonia, Eluent B: acetonitrile;Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL/min;Temperature: 60° C.; Injection: 2 μL; DAD scan: 210-400 nm; ELSD.

UPLC-MS Method E

Instrument: Waters Acquity UPLC-MS; Column: XBridge BEH C18 2.5 μm2.1×50 mm; Eluent A: 10 mM ammonium bicarbonate pH 10, Eluent B:acetonitrile; Gradient: 50-98% B in 0.80 min, hold at 98% B to 1.30 min;Flow rate 0.8 mL/min; Detection: Waters Acquity Autosampler (UPLC LG 500nm).

UPLC-MS Method F

Instrument: Waters Acquity UPLC-MS; Column: XBridge BEH C18 2.5 μm2.1×50 mm; Eluent A: 10 mM ammonium bicarbonate pH 10, Eluent B:acetonitrile; Gradient: 2-98% B in 0.80 min, hold at 98% B to 1.30 min;Flow rate 0.8 mL/min; Detection: Waters Acquity Autosampler (UPLC LG 500nm).

UPLC-MS Method G

Instrument: Waters Acquity UPLC-MS; Column: XBridge BEH C18 2.5 μm2.1×50 mm; Eluent A: 10 mM ammonium bicarbonate pH 10, Eluent B:acetonitrile; Gradient: 60-98% B in 0.80 min, hold at 98% B to 1.30 min;Flow rate 0.8 mL/min; Detection: Waters Acquity Autosampler (UPLC LG 500nm).

UPLC-MS Method H

Instrument: Waters Acquity UPLC-MS; Column: XBridge BEH C18 2.5 μm2.1×50 mm; Eluent A: 10 mM ammonium bicarbonate pH 10, Eluent B:acetonitrile; Gradient: 2-98% B in 4.00 min, hold at 98% B to 4.70 min;Flow rate 0.8 mL/min; Detection: Waters Acquity Autosampler (UPLC LG 500nm).

LC-MS Standard Procedures

Analytical LC-MS was performed as described below. The masses (m/z) arereported from the positive mode electrospray ionisation unless thenegative mode is indicated (ES−).

LC-MS Method A

Instrument: Water Alliance 2695 HPLC Pump; Column: XBridge C18 2.5 μm2.1×20 mm; Eluent A: 10 mM ammonium bicarbonate pH 10, Eluent B:acetonitrile; Gradient: hold at 50% B to 0.18 min, 50-95% B to 2.00 min,hold at 95% B to 2.60 min; Flow rate 1 mL/min; Detection: Waters 996 PDA215-350 nm; Run Time: 3.10 min.

LC-MS Method B

Instrument: Water Alliance 2695 HPLC Pump; Column: XBridge C18 2.5 μm2.1×20 mm; Eluent A: 10 mM ammonium bicarbonate pH 10, Eluent B:acetonitrile; Gradient: 0% B to 0.18 min, 0-95% B to 2.00 min, hold at95% B to 2.60 min; Flow rate 1 mL/min; Detection: Waters 996 PDA 215-350nm; Run Time: 3.10 min.

LC-MS Method C

Instrument: Water Alliance 2695 HPLC Pump; Column: XBridge C18 2.5 μm2.1×20 mm; Eluent A: 10 mM ammonium bicarbonate pH 10, Eluent B:acetonitrile; Gradient: 20-70% B in 2.00 min, 70-95% B to 2.10, hold at95% B to 2.60 min; Flow rate 1 mL/min; Detection: Waters 996 PDA 215-350nm; Run Time: 3.10 min.

NMR peak forms are stated as they appear in the spectra, possible higherorder effects have not been considered.

The obtained benzimidazoles of general formula (I) may be chiral and maybe separated into their diastereomers and/or enantiomers by chiral HPLC.

Intermediates

Intermediate 1-1

(±)5-bromo-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine

Step 1: (±) 4-bromo-2-nitro-N-(3,3,5-trimethylcyclohexyl)aniline

17 g (77.27 mmol) 4-Bromo-1-fluoro-2-nitrobenzene (commerciallyavailable, CAS-RN: 364-73-8)) were given in 308 mL tetrahydrofurane.After addition of 11.75 g (84.99 mmol) potassium carbonate the reactionmixture was stirred for 10 min at room temperature. 10.92 g (77.27 mmol)3,3,5-trimethylcyclohexanamine (mixture of stereoisomers, commerciallyavailable, CAS-RN: 15901-42-5) were added and the reaction mixture washeated at 50° C. over night. The reaction mixture was diluted with ethylacetate and water. The aqueous phase was reextracted twice with ethylacetate and the combined organic extracts were dried (sodium sulfate).The solvent was evaporated yielding 28.3 g (97% ) of the desired productas a mixture of stereoisomers. UPLC-MS: R_(t)=1.78 min; m/z=341 (ES+,M+1). ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.72-1.03 (m, 11H), 1.13 (t,1H), 1.29-1.39 (m, 1H), 1.59-1.89 (m, 2H), 1.91-2.05 (m, 1H), 3.70-3.90(m, 1H), 7.12 (d, 1H), 7.64 (dd, 1H), 7.82 (d, 1H), 8.15 (d, 1H).

Step 2: (±)4-bromo-N¹-[(cis)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine

28.3 g (82.93 mmol) (±)4-Bromo-2-nitro-N-(3,3,5-trimethylcyclohexyl)aniline, described in step1, were dissolved in methanol (366 mL). After addition of 66.83 g (290mmol) tin(II)chloride dihydrate the reaction mixture was stirred for 12hours at 70° C. The reaction mixture was evaporated to dryness and theresidue was diluted with ethyl acetate. After washing with water andbrine the organic phase was dried and the solvent was removed.Purification of the residue by column chromatography (eluents:hexane/ethyl acetate) yielded 27 g (99% ) of a single stereoisomer (cisdiastereoisomer as racemate). UPLC-MS: R_(t)=1.54 min; m/z=311 (ES+,M+1). ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.72-1.02 (m, 11H), 1.09-1.21(m, 1H), 1.29-1.39 (m, 1H), 1.54-1.75 (m, 2H), 1.85-2.02 (m, 1H),3.40-3.60 (m, 1H), 6.74-6.92 (m, 2H), 6.99 (d, 1H).

Step 3: (±)5-bromo-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine

5.00 g (16.06 mmol) (±)4-Bromo-N¹-[(cis)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine,intermediate 1-1, step 2, were dissolved in 320 mL tetrahydrofurane.After addition of 3.52 g (16.06 mmol)4-(trifluoromethoxy)-phenylisothiocyanate (commercially available,CAS-RN: 64285-95-6) and 4.05 g (32.13 mmol) N,N′-diisopropylcarbodiimidethe reaction mixture was stirred at 70° C. for two hours. The reactionmixture was evaporated to dryness and the residue was diluted withdichloromethane. After washing with brine and water the organic phasewas dried (Na₂SO₄) and filtered. The solvent was removed and the residuepurified by column chromatography to yield 1.41 g (16.8% ) of the titlecompound. UPLC-MS: R_(t)=1.69 min; m/z=496.1 (ES+, M+1). ¹H-NMR (300MHz, DMSO-d₆): δ [ppm]=0.91-1.21 (m, 10H), 1.32-1.50 (m, 2H), 1.65-2.09(m, 4H), 4.58-4.73 (m, 1H), 7.08-7.18 (m, 1H), 7.27-7.38 (m, 2H),7.46-7.58 (m, 2H), 7.75-7.86 (m, 2H), 9.12 (s, 1H).

Intermediate 1-2

(±)5-bromo-N-{4-[(trifluoromethyl)sulfanyl]phenyl}-1-[(cis)-3,3,5-trimethylcyclo-hexyl]-1H-benzimidazol-2-amine

1.5 g (4.82 mmol) (±)4-Bromo-N¹-[(cis)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine,intermediate 1-1, step 2, were dissolved in 96 mL tetrahydrofurane.After addition of 1.13 g (4.82 mmol)1-isothiocyanato-4-[(trifluoromethyl)sulfanyl]benzene (commerciallyavailable, CAS-RN: 189281-95-6) and 1.22 g (9.64 mmol)N,N′-diisopropylcarbodiimide the reaction mixture was stirred at 70° C.for two hours. The reaction mixture was evaporated to dryness and theresidue was diluted with dichloromethane. After washing with brine andwater the organic phase was dried (Na₂SO₄) and filtered. The solvent wasremoved and the residue purified by column chromatography yielding 1.06g (40.8% ) of the title compound. UPLC-MS: R_(t)=1.81 min; m/z=512.10(ES+, M+1). ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.90-1.18 (m, 10H),1.32-1.48 (m, 2H), 1.68-1.80 (m, 1H), 1.80-1.93 (m, 2H), 2.01 (t, 1H),4.68 (t, 1H), 7.12-7.20 (m, 1H), 7.52-7.62 (m, 2H), 7.65 (d, 2H), 7.83(d, 2H), 9.35 (s, 1H).

Intermediate 1-3

(±)5-bromo-N-{4-[(trifluoromethyl)]phenyl}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine

1.5 g (4.82 mmol) (±)4-Bromo-N¹-[(cis)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine,intermediate 1-1, step 2, were dissolved in 96 mL tetrahydrofurane.After addition of 0.98 g (4.82 mmol)1-isothiocyanato-4-(trifluoromethyl)benzene (commercially available,CAS-RN: 1645-65-4) and 1.22 g (9.64 mmol) N,N′-diisopropylcarbodiimidethe reaction mixture was stirred at 70° C. for two hours. The reactionmixture was evaporated to dryness and the residue was diluted withdichloromethane. After washing with brine and water the organic phasewas dried (Na₂SO₄) and filtered. The solvent was removed and the residuepurified by column chromatography yielding 0.88 g (34.4% ) of the titlecompound. UPLC-MS: R_(t)=1.77 min; m/z=480.1 (ES+, M+1). ¹H-NMR (300MHz, DMSO-d₆): δ [ppm]=0.82-1.19 (m, 10H), 1.31-1.50 (m, 2H), 1.63-2.09(m, 4H), 4.68 (t, 1H), 7.09-7.19 (m, 1H), 7.52-7.62 (m, 2H), 7.68 (d,2H), 7.90 (d, 2H), 9.38 (s, 1H).

Intermediate 1-4

5-bromo-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-N-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-amine

Step 1:4-bromo-5-methyl-2-nitro-N-(3,3,5,5-tetramethylcyclohexyl)aniline

To a solution of 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (CAS No.[170098-98-3]; 1.99 g, 8.49 mmol) in DMF (20 mL) withN,N-diisopropylethylamine (4.43 mL, 25.47 mmol) was added3,3,5,5-tetramethylcyclohexanamine (CAS No. [32939-18-7]; 1.45 g, 9.34mmol). The reaction was heated at 60° C. for 4 h. The reaction mixturewas poured into water (100 mL) and extracted with diethyl ether (3×40mL). The combined organics were washed with saturated brine solution (20mL), dried over solid sodium sulfate and concentrated under vacuum togive the title compound (3.0 g, 91% ) as an orange solid. UPLC-MS(Method E): R_(t)=2.49 min; m/z=369/371 (M+H)⁺. ¹H-NMR (300 MHz, CDCl₃):δ [ppm]=0.96 (s, 6H), 1.13 (s, 6H), 0.96-1.35 (m, 4H), 1.84 (s, 2H),2.38 (s, 3H), 6.71 (s, 1H), 7.92 (d, 1H), 8.32 (s, 1H).

Step 2:4-bromo-5-methyl-N-(3,3,5,5-tetramethylcyclohexyl)benzene-1,2-diamine

To a solution of4-bromo-5-methyl-2-nitro-N-(3,3,5,5-tetramethylcyclohexyl)aniline (3.04g, 8.23 mmol) from step 1 in water (35 mL) and ethanol (72 mL) wereadded iron powder (2.29 g, 41.2 mmol) and ammonium chloride (2.20 g,41.2 mmol) and the reaction was heated at 60° C. for 1.5 h. The reactionwas cooled and diluted with ethyl acetate (50 mL) and water (50 mL). Themixture was filtered through celite washing with ethyl acetate (6×50mL). The filtrate was further diluted with water (100 mL). The layerswere split and the aqueous extracted into ethyl acetate (2×50 mL). Thecombined organics were dried over solid sodium sulfate then concentratedunder vacuum. The crude material was purified by flash silica columnchromatography (ethyl acetate/hepane) to give the title compound (2.64g, 94% ) as a brown solid. LC-MS (Method A): R_(t)=1.84 (91% );m/z=339/341 (M+H)⁺. ¹H-NMR (300 MHz, CDCl₃): δ [ppm]=0.91 (s, 6H), 1.06(s, 6H), 0.99-1.24 (m, 4H), 1.82 (d, 2H), 2.27 (s, 3H), 3.61(br s, 2H),6.83-6.97 (m, 2H).

Step 3:5-bromo-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-N-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-amine

To a solution of4-bromo-5-methyl-N-(3,3,5,5-tetramethylcyclohexyl)benzene-1,2-diamine(1.47 g, 4.33 mmol) from step 2 in tetrahydrofuran (32 mL) was added4-(trifluoromethoxy)phenylisothiocyanate (CAS No. [64285-95-6]; 0.65 mL,4.33 mmol) and the reaction was stirred at room temperature for 1 h 45min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96g, 4.98 mmol) was added and the reaction was heated at 70° C. for 1 h.The reaction was cooled and poured into a saturated sodium bicarbonatesolution (20 mL) then extracted with ethyl acetate (3×20 mL). Thecombined organics were washed with brine (20 mL), dried over solidsodium sulfate and concentrated under vacuum. The crude material waspurified by flash silica column chromatography (ethyl acetate/heptane)to give the title compound (1.83 g, 81% ) as a brown solid. UPLC-MS(Method F): R_(t)=1.20 min; m/z=524/526 (M+H)⁺. ¹H-NMR (300 MHz, CDCl₃):δ [ppm]=0.93 (s, 6H), 0.98 (s, 6H), 1.21-1.29 (m, 2H), 1.61 (d, 2H),1.89 (t, 2H), 2.51 (s, 3H), 4.38 (t, 1H), 7.10-7.30 (m, 6H), 7.73 (s,1H).

Intermediate 1-5

N-[(1E)-1-(dimethylamino)ethylidene]-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxamide

Step 1: methyl2-methyl-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate

To a solution of methyl 4-fluoro-2-methyl-5-nitrobenzoate (CAS No.[1163287-01-1]; 7.80 g, 36.6 mmol) in DMF (80 mL) were addedN,N-diisopropylethylamine (19.11 mL, 109.77 mmol) and3,3,5,5-tetramethylcyclohexanamine (CAS No. [32939-18-7]; 6.25 g 40.2mmol). A further 20 mL of DMF was added to fully mobilise the solids,then the reaction was heated for 2.5 h at 60° C. The reaction mixturewas poured into water (100 mL) and extracted with ethyl acetate (4×60mL). The combined organics were washed with saturated brine solution,dried over solid sodium sulfate, concentrated under vacuum andazeotroped with toluene to give the title compound (12.56 g, 98% ) as ayellow solid. UPLC-MS (Method F): R_(t)=1.15 min; m/z=349 (M+H)⁺. ¹H-NMR(300 MHz, CDCl₃): δ [ppm]=0.97 (s, 6H), 1.17 (s, 6H), 0.97-1.36 (m, 4H),1.84 (d, 2H), 2.62 (s, 3H), 3.83 (s, 3H), 3.75-3.90 (m, 1H), 6.62 (s,1H), 8.17 (d, 1H), 8.87 (s, 1H).

Step 2: methyl5-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate

To a solution of methyl2-methyl-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate (3.04g, 8.23 mmol) from step 1 in water (140 mL) and ethanol (288 mL) wereadded iron powder (10.06 g, 180.2 mmol) and ammonium chloride (9.64 g,180 mmol). The reaction was heated at 60° C. for 4 h. The reactionmixture was cooled and diluted with ethyl acetate (100 mL) and water(100 mL). The mixture was filtered through celite washing with ethylacetate (6×75 mL). The filtrate was further diluted with water (100 mL).The layers were split and the aqueous extracted into ethyl acetate(3×100 mL). The combined organics were dried with sodium sulfate thenconcentrated under vacuum. The crude material was purified by flashsilica column chromatography (ethyl acetate/heptane) to give the titlecompound (10.2 g, 89% ) as a brown solid. LC-MS (Method A): R_(t)=1.33min; m/z=319 (M+H)⁺. ¹H-NMR (300 MHz, CDCl₃): δ [ppm]=0.93 (s, 6H), 1.12(s, 6H), 0.93-1.33 (m, 2H), 1.87 (d, 2H), 2.53 (s, 3H), 3.65 (t, 2H),3.81 (s, 3H), 6.42 (s, 1H), 7.39 (s, 3H).

Step 3: methyl6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylate

To a solution of methyl5-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate (10.2g, 32.1 mmol) from step 2 in tetrahydrofuran (200 mL) was added4-(trifluoromethoxy)phenylisothiocyanate (CAS No. [64285-95-6]; 6.52 g,32.1 mmol). The reaction was stirred at room temperature for 50 min.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.07 g,36.91 mmol) was then added and the reaction heated at 75° C. for 18 h.The reaction was cooled and poured into a saturated solution of sodiumbicarbonate (100 mL) then extracted with ethyl acetate (3×100 mL). Thecombined organics were washed with brine, dried over sodium sulfate,filtered and concentrated under vacuum. The crude material was purifiedby flash silica column chromatography (ethyl acetate/heptane) to givethe desired ester (15.3 g, 94% ) as a sandy yellow foam. UPLC-MS (MethodF): R_(t)=1.12 min; m/z=504 (M+H)⁺. ¹H-NMR (300 MHz, CDCl₃): δ[ppm]=0.92 (s, 6H), 0.99 (s, 6H), 1.10-1.30 (m, 2H), 1.65 (d, 2H), 1.92(t, 2H), 2.72 (s, 3H), 3.90 (s, 3H), 4.42 (t, 1H), 7.12-7.30 (m, 6H),8.16 (s, 1H).

Step 4:6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylicacid

To a solution of methyl6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylate(2.00 g, 3.97 mmol) from step 3 in methanol (30 mL) and water (3 mL) wasadded sodium hydroxide (318 mg, 7.94 mmol). The reaction was stirred at70° C. overnight. The mixture was cooled and acidified with saturatedammonium chloride solution to pH 5. The precipitate was collected byfiltration and washed with water (300 mL). The material was then airdried to give the desired acid (1.80 g, 93% ) as a colourless solid.LC-MS (Method B): R_(t)=1.94 min; m/z=490 (M+H)⁺. ¹H-NMR (300 MHz,DMSO-d₆): δ [ppm]=0.95 (s, 6H), 1.07 (s, 6H), 1.20-1.37 (m, 2H), 1.52(d, 2H), 2.02 (t, 2H), 2.60 (s, 3H), 4.57 (t, 1H), 7.30 (d, 2H), 7.44(s, 1H), 7.61 (d, 2H), 7.85 (s, 1H), 9.00 (s, 1H).

Step 5:6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxamide

1,1′-Carbonyldiimidazole (331 mg, 2.04 mmol) was added to a solution of6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylicacid (500 mg, 1.02 mmol) from step 4 in DMF (25 mL). The reaction wasstirred for 3 h at room temperature upon which ammonium carbonate (1.47g, 15.30 mmol) was added. The reaction was stirred at room temperaturefor 3 days and at 50° C. for 2 days. The reaction was cooled and water(100 mL) and ethyl acetate (300 mL) were added. The layers wereseparated and the organics were washed with brine (50 mL). The organiclayer was dried over solid sodium sulfate and concentrated under vacuum.The product was then triturated with diethyl ether to give the titlecompound (550 mg, 97% ) as a colourless solid. UPLC-MS (Method G):R_(t)=0.57 min; m/z=489 (M+H)⁺. ¹H-NMR (300 MHz, CDCl₃): δ [ppm]=0.99(s, 6H), 1.00 (s, 6H), 1.20-1.40 (m, 2H), 1.60-1.67 (m, 4H), 1.94 (t,2H), 2.64 (s, 3H), 4.40 (m, 1H), 7.20-7.30 (m, 5H), 7.70 (s, 1H).

Step 6:N-[(1E)-1-(dimethylamino)ethylidene]-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxamide

To a solution of6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxamide(50 mg, 0.10 mmol) from step 5 in toluene (10 mL)N,N-dimethylacetamidedimethyl acetal (136 mg, 1.02 mmol) was added. Thereaction mixture was stirred at 50° C. for 5 h, then concentrated undervacuum to give the title compound (50 mg, 88% ) as a pale yellow solid.The obtained material was used without further purification. LC-MS(Method A): R_(t)=1.57 min; m/z=558 (M+H)⁺.

Intermediate 1-6

N′-Acetyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carbohydrazide

Step 1: Methyl 3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate

0.7 g (3.52 mmol) Methyl-4-fluoro-3-nitrobenzoate (commerciallyavailable) and 0.674 g (3.52 mmol) 3,3,5,5-tetramethylcyclohexanaminehydrochloride (commercially available) were given in 7.0 mLtetrahydrofuran. After addition of 0.38 g (2.76 mmol) potassiumcarbonate the reaction mixture was heated at 50° C. for 24 hours. Thereaction mixture was diluted with water The aqueous phase was washedwith ethyl acetate and dichloromethane. The combined organic extractswere dired over sodium sulfate. After removal of the solvent 1.19 g ofcrude product was used without prior purification in the next step.

Step 2: Methyl-3-amino-4-{[3,3,5,5-tetramethylcyclohexyl]amino}benzoate

1.8 g (5.4 mmol) Methyl3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate were dissolvedin ethyl acetate (120 mL). After addition of 115 mg (1.10 mmol) Pd/C thereaction mixture was stirred under a hydrogen atmosphere for 20 h atroom temperature. After the catalyst was filtered off and removal ofsolvent the crude product was used without prior purifications.

Step 3:Methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazole-5-carboxylate

To a solution ofmethyl-3-amino-4-{[3,3,5,5-tetramethylcyclohexyl]amino}benzoate (0.2 g,0.66 mmol) from step 2 in tetrahydrofuran (5.0 mL) was added4-(trifluoromethoxy)phenylisothiocyanate (CAS No. [64285-95-6]; 117 mg,0.66 mmol). The reaction was stirred at room temperature for 50 min.N,N′-diisopropylcarbodiimide (166 mg, 1.31 mmol) was then added and thereaction heated at 70° C. for 24 h. After cooling to room temperature,removal of the solvent and subsequent purification of the crude product,250 mg (80% ) of the desired product was obtained. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 0.97 (s, 6 H), 1.12 (s, 6 H), 1.22-1.38 (m, 2 H),1.55-1.59 (m, 2 H), 2.00-2.09 (m, 2 H), 3.83 (s, 3 H), 4.52-4.77 (m, 1H), 7.33 (d, 2 H), 7.63-7.79 (m, 4 H), 7.94 (s, 1 H), 9.13 (s, 1 H) MS:(ESI+, M+1): 490.

Step 4:2-{[4-(Trifluoromethoxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazole-5-carboxylicacid

Methyl2-{[4-(trifluoromethoxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazole-5-carboxylate(100 mg, 0.20 mmol) was dissolved in 0.9 mL dioxane. After addition of9.78 mg (0.41 mmol) LiOH and 0.3 mL water the reaction mixture wasstirred at 70° C. for 2.5 hours and then evaporated to dryness. Theresidue was treated with water (10 mL) and acidified with HCl (1N) topH4. After stirring at room temperature for two hours the crystals weresucked off and washed with water yielding 100 mg (>100% ) of the desiredcompound which was used in the next step without further purification.

Step 5:N′-Acetyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]-amino}-1H-benzimidazole-5-carbohydrazide

To a solution of2-{[4-(trifluoromethoxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazole-5-carboxylicacid (100 mg, 0.21 mmol), step 1, in tetrahydrofuran (5.0 mL) was addedaceto hydrazide (18 mg, 0.23 mmol) in the presence of HATU (88 mg, 0.23mmol) and N,N-diisopropylethylamine (80 μL, 0.44 mmol). The reactionmixture was stirred at 60° C. for 24 h. After removal of the solvent thecrude product (330 mg) was used in the next step without furtherpurification.

Intermediate 1-7

N′-Hydroxy-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]-amino}-1H-benzimidazole-5-carboximidamide

Step 1: 3-Nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzonitrile

0.348 g (2.09 mmol) 4-Fluoro-3-nitrobenzonitrile (commerciallyavailable) and 0.402 g (2.09 mmol) 3,3,5,5-tetramethylcyclohexanaminehydrochloride (commercially available) were given in 7.0 mLtetrahydrofuran. After addition of 0.608 g (4.40 mmol) potassiumcarbonate the reaction mixture was heated at 50° C. for 20 hours. Thereaction mixture was diluted with saturated aqueous sodium chloridesolution. The aqueous phase was washed with ethyl acetate anddichloromethane. The combined organic extracts were dired over sodiumsulfate. After removal of the solvent 0.630 g (98% ) of crude productwas used without prior purification in the next step. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 0.91 (s, 6 H) 1.03-1.39 (m, 10 H) 1.72-1.76 (m, 2 H)3.79-4.07 (m, 1 H) 7.19 (d, 1 H) 7.84 (dd, 1 H) 8.14 (d, 1 H) 8.51 (d 1H)

Step 2: 3-Amino-4-{[3,3,5,5-tetramethylcyclohexyl]amino}benzonitrile

0.1 g (0.33 mmol)3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzonitrile weredissolved in tetrahydrofurane (5.0 mL). After addition of 7 mg (0.07mmol) Pd/C the reaction mixture was stirred under a hydrogen atmospherefor 3 days at room temperature. After the catalyst was filtered off andremoval of solvent the crude product was used without priorpurifications.

Step 3:1-(3,3,5,5-Tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carbonitrile

105 mg (0.33 mmol)3-Amino-4-(3,3,5,5-tetramethylcyclohexylamino)benzonitrile weredissolved in 1.9 mL tetrahydrofurane. 72.9 mg (0.33 mmol)4-Isothiocyanatophenyl trifluoromethyl ether and 84 mgN,N′-diisopropylcarbodiimide were added and the reaction mixture wasstirred at 70° C. for 17 hours. The solvent was removed yielding 211 mg(>100% ) of the desired compound which was used in the next step withoutfurther purification.

Step 4:N′-Hydroxy-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]-amino}-1H-benzimidazole-5-carboximidamide

To a solution of1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carbonitrile,(211 mg, step 3) in ethanol (3 mL), was added hydroxylamine (85 μL, 1.4mmol, 50% solution in water). The reaction was stirred at roomtemperature for 20 h. After removal of the solvent 245 mg of thecompound were obtained as crude product which was used without furtherpurification in the next step.

Intermediate 1-8

(±)2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(trans)-3,3,5-trimethylcyclohexyl]-1H-benzimidazole-5-carbonitrile

Step 1: (±)3-nitro-4-{[(trans)-3,3,5-trimethylcyclohexyl]amino}benzonitrile

300 mg (1.8 mmol) 4-Fluor-3-nitrobenzonitril (commercially available)and 255 mg (1.8 mmol) 3,3,5-trimethylcyclohexanamine (mixture ofstereoisomers, commercially available) were dissolved in 5 mLtetrahydrofurane. After addition of 524 mg (138 mmol) potassiumcarbonate the reaction mixture was heated at 50° C. for 45 hours. Thesolvent was removed and the residue submitted to column chromatography(Biotage SNAP, KP-SIL, eluents: hexane/ethyl acetate) yielding 0.27 g(52% ) of the trans diastereomer (as racemate). ¹H-NMR (300 MHz, CDCl₃):δ [ppm]=0.94-1.03 (m, 6H), 1.09 (s, 3H), 1.25-1.38 (m, 2H), 1.45-1.56(m, 2H), 1.75 (m, 1H), 1.90 (m, 2H), 4.0 (m, 1H), 6.93 (d, 1H), 7.60 (m,1H), 8.3 (m, 1H). UPLC-MS (Method A): R_(t)=1.56 min; MS (ES+, M+1)288.1; MS (ES−, M−1) 286.1.

Step 2: (±)3-amino-4-{[(trans)-3,3,5-trimethylcyclohexyl]amino}benzonitrile

200 mg (0.69 mmol) (±)3-Nitro-4-{[(trans)-3,3,5-trimethylcyclohexyl]amino}benzonitrile, step1, were dissolved in ethyl acetate (10 mL). After addition of 20 mg Pd/C(10% Pd) the reaction mixture was stirred under a hydrogen atmospherefor two hours at room temperature. The catalyst was filtered off via aglass fibre filter and washed with ethyl acetate. The solvent wasevaporated and the crude product, (175 mg, 97% yield, trans diastereomeras racemate) was used in the next step without further purification.¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.86 (s, 3H), 0.92 (m, 6H), 1.20-1.41(m, 4H), 1.65 (m, 2H), 2.06 (m, 1H), 3.71 (m, 1H), 4.89 (d, 1H), 5.01(s, 2H), 6.43 (d, 1H), 6.91 (dd, 1H). UPLC-MS (Method B): R_(t)=1.58min; MS (ES+, M+1) 443.3; MS (ES−, M−1) 441.3.

Step 3: (±)2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(trans)-3,3,5-trimethylcyclohexyl]-1H-benzimidazole-5-carbonitrile

225 mg (0.87 mmol) (±)3-Amino-4-{[(trans)-3,3,5-trimethylcyclohexyl]-amino}benzonitrile, step2, and 191 mg of 1-isothiocyanato-4-(trifluoromethoxy)benzene werereacted in an analogous manner to Intermediate 1-7 step 1, yielding 168mg (41% ) of the desired compound. ¹H-NMR (300 MHz, DMSO-d₆): δ[ppm]=0.98 (s, 3H), 1.06-1.15 (s, 6H), 1.20-1.30 (m, 2H) 1.40-1.53 (m,2H), 1.42-1.55 (m, 2H), 1.64 (br., m, 1H), 2.19-2.37 (m, 2H), 4.74 (br.m, 1H), 7.34 (s, 1H), 7.37 (s, 1H), 7.41(dd, 1H), 7.73 (d, 1H) 7.70-7.82(m, 3H), 9.23 (s, 1H). UPLC-MS (Method A): R_(t)=1.60 min; MS (ES+, M+1)288.1; MS (ES−, M−1) 286.1.

Intermediate 1-9

5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine

3 g (6.04 mmol) (±)5-Bromo-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine,intermediate 1-1, 2.3 g (9.07 mmol) bis(pinacolato)diboron, 1.78 g(19.13 mmol) potassium acetate and 0.49 g (0.60 mmol)1,1′-(bisdiphenylphosphino)ferrocenedichloropalladium(II) were heated in35 mL THF (degassed) at 80° C. for three hours. Due to an incompletereaction additional catalyst was added and heating was continued at 100°C. for four hours. The reaction mixture was cooled, diluted with waterand extracted three times with dichloromethane. The combined organicextracts were washed with brine and dried (Na₂SO₄). The solvent wasevaporated and the residue (2.62 g=71.2% ) was used without furtherpurification. UPLC-MS: R_(t)=1.60 min; m/z=544.3 (M+1). ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm]=0.91-1.10 (m, 10H), 1.29 (s, 12H), 1.40 (d, 2H),1.68-1.95 (m, 3H), 2.02 (t, 1H), 4.65 (t, 1H), 7.28-7.39 (m, 3H), 7.53(d, 1H), 7.66 (s, 1H), 7.79 (d, 2H), 9.04 (s, 1H).

Intermediate 1-10

ethyl[5-(2,4-dioxo-1,3-oxazolidin-5-yl)-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-2-yl][4-(trifluoromethoxy)phenyl]carbamate

Step 1:[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]methanol

Lithium aluminium hydride (151 mg, 3.90 mmol) was suspended intetrahydrofuran (15 mL) under argon then cooled to 0° C. A solution ofmethyl6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylate(1.0 g, 1.98 mmol) from step 3 of intermediate 1-5 in tetrahydrofuran(10 mL) was added drop-wise. The reaction was stirred at 0° C. for 30min then at room temperate for 1 h. Sodium sulfate decahydrate was addeduntil evolution of gas ceased. The mixture was then filtered throughcelite, washing with ethyl acetate. The filtrate was evaporated to givea pale brown waxy solid, which was triturated with dichloromethane togive the title compound (0.69 g, 73% ) as a white powder. UPLC-MS(Method F) R_(t)=1.02 min; m/z=476 (M+H)⁺. ¹H-NMR (300 MHz, CDCl₃): δ[ppm]=0.91 (s, 6H), 0.97 (s, 6H), 1.28 (m, 2H), 1.60 (d, 2H), 1.98 (m,4H), 2,49 (s, 3H), 4.41 (tt, 1H), 4.75 (s, 2H), 7.17 (m, 4H), 7.20 (s,1H), 7.56 (s, 1H)

Step 2:6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]-amino}-1H-benzimidazole-5-carbaldehyde

[6-Methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]methanol(690 mg, 1.40 mmol) from step 1 was dissolved in tetrahydrofuran (15mL), stabilised 2-iodoxybenzoic acid (1.08 g, 1.70 mmol, 45 wt. % ) wasadded and the flask was wrapped in foil. The reaction was stirred atroom temperature for 8 h. The purple solution was diluted with ethylacetate then washed twice with a saturated sodium bicarbonate solution.The aqueous layer was extracted with ethyl acetate and the combinedorganic layers were washed with brine, dried over sodium sulfate andconcentrated under vacuum to give an indigo solid. The crude wastriturated with heptane, filtered and washed with heptane to give thetitle compound (415 mg, 60% ) as a pale reddish solid. UPLC-MS (MethodG): R_(t)=0.86 min; m/z=474 (M+H)⁺. ¹H-NMR (300 MHz, CDCl₃): δ[ppm]=1.00 (s, 12H), 1.21 (d, 1H), 1.34 (d, 1H), 1.68 (d, 2H), 1.97 (d,2H), 2.79 (s, 3H), 4.47 (m, 1H), 7.17 (m, 3H), 7.32 (m, 2H), 7.96 (s,1H) 10.24 (s, 1H).

Step 3:cyano[2-{(ethoxycarbonyl)[4-(trifluoromethoxy)phenyl]amino}-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]methylethyl carbonate

To a solution of6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)-phenyl]amino}-1H-benzimidazole-5-carbaldehyde(50 mg, 0.11 mmol) from step 2 in acetonitrile (4 mL), ethylcyanoformate (13 mg, 0.13 mmol) and 4-dimethyl-aminopyridine (2 mg, 0.02mmol) were added. The reaction mixture was stirred at room temperaturefor 3 h then additional ethyl cyanoformate (13 mg, 0.13 mmol) was added.After a further 6 h the reaction was quenched by addition of brine (20mL) and the mixture was extracted with ethyl acetate (3×20 mL). Thecombined organic layers were dried over solid sodium sulfate andconcentrated under vacuum to give the title compound (51 mg, 75% ) as ayellow oil, which was used without further purification. UPLC-MS (MethodG): R_(t)=0.96 min; m/z=645 (M+H)⁺. ¹H-NMR (300 MHz, CDCl₃): δ[ppm]=0.85-1.10 (m, 12H), 1.10-1.70 (m, 10H), 1.85-2.00 (m, 2H), 2.56(s, 3H), 4-00-4.20 (m, 5H), 6.47 (s, 1H), 7.22 (d, 2H), 7.40 (d, 2H),7.99 (s, 1H), 8.26 (m, 1H).

Step 4:2-amino-1-[2-{(ethoxycarbonyl)[4-(trifluoromethoxy)phenyl]amino}-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]-2-oxoethylethyl carbonate

Cyano[2-{(ethoxycarbonyl)[4-(trifluoromethoxy)phenyl]amino}-6-methyl-1-(3,3,5,5-tetra-methylcyclohexyl)-1H-benzimidazol-5-yl]methylethyl carbonate (51 mg, 0.08 mmol) from step 3 was dissolved inhydrochloric acid (5 mL, 20 mmol, 4 M in dioxane), aqueous hydrochloricacid (5 mL, 55 mmol, 11 M) was added at 0° C. and the reaction wasstirred at this temperature for 30 min and at room temperature for 4 h.The reaction was quenched by addition of water (100 mL) and theresulting precipitate was collected by filtration. The solid was washedwith water (50 mL) then azeotroped with toluene (3×15 mL) to give thetitle compound (56 mg, 89% ) as a colourless solid. UPLC-MS (Method G):R_(t)=0.76 min; m/z=663 (M+H)⁺. ¹H-NMR (300 MHz, CDCl₃): δ[ppm]=0.85-1.10 (m, 12H), 1.10-1.70 (m, 10H), 1.85-2.00 (m, 2H), 2.67(s, 3H), 4-00-4.20 (m, 5H), 5.64 (s, 1H) 6.28 (s, 1H), 6.47 (s, 1H),7.20-8.00 (m, 6H).

Step 5: ethyl[5-(2,4-dioxo-1,3-oxazolidin-5-yl)-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-2-yl][4-(trifluoromethoxy)phenyl]carbamate

2-Amino-1-[2-{(ethoxycarbonyl)[4-(trifluoromethoxy)phenyl]amino}-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]-2-oxoethylethyl carbonate (56 mg, 0.07 mmol) from step 4 was dissolved inacetonitrile (5 mL), 1,8-diazabicyclo(5.4.0)undec-7-ene (13 mg, 0.08mmol) was added and the reaction stirred at room temperature for 5 h.The solvent was removed by evaporation and the residue dissolved inethyl acetate (50 mL). The organic layer was washed with water (15 mL)and brine (15 mL), dried over solid sodium sulfate and concentratedunder vacuum to give the title compound (42 mg, 94% ) as yellow oil,which was used without further purification. UPLC-MS (Method F):R_(t)=0.78 min; m/z=617 (M+H)⁺. ¹H-NMR (300 MHz, CDCl₃): δ[ppm]=0.85-1.60 (m, 17H), 1.60-180 (m, 2H), 1.94 (t, 2H), 2.61 (s, 3H),4.16 (t, 2H), 4.40 (m, 1H), 6.22 (br s, NH), 6.80 (m, 3H), 6.99 (d, 1H),7.07 (d, 2H), 7.45 (d, 1H).

Intermediate 1-11

N-hydroxy-2-{2-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,3-dioxolan-2-yl}acetamide

Step 1: ethyl3-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)-phenyl]amino}-1H-benzimidazol-5-yl]-3-oxopropanoate

6-Methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylicacid (200 mg, 0.98 mmol) from step 4 of intermediate 1-5 was added to asuspension of 1,1′-carbonyldiimidazole (166 mg, 0.41 mmol) inN,N-dimethylformamide (15 mL). The resulting mixture was stirred for 4 hat 50° C. Magnesium chloride (93 mg, 0.98 mmol) and ethyl potassiummalonate (167 mg, 0.98 mmol) were added and the solution stirred at 110°C. overnight. The reaction was quenched by addition of water (100 mL)and the resulting precipitate was collected by vacuum filtration. Thesolid was dissolved in ethyl acetate (100 mL) and washed twice withaqueous hydrochloridic acid (1 M, 50 mL). The organic layer was thendried over solid sodium sulfate and concentrated under vacuum. The crudematerial was purified by flash silica column chromatography(dichloromethane) to give the title compound (210 mg, 92% ) as a paleyellow solid. UPLC-MS (Method F): R_(t)=1.08 min; m/z=560 (M+H)⁺. ¹H-NMR(300 MHz, CDCl₃): δ [ppm]=1.03 (s, 6H), 1.21 (s, 6 H), 1.10-1.40 (m,5H), 1.60-1.70 (m, 2H), 1.85-2.00 (m, 2H), 2.56 (s, 3H), 4.03 (s, 2H),4.21 (q, 2H, 4.38 (m, 1H), 7.10-7.30 (m, 5H), 7.95 (s, 1H).

Step 2: ethyl{2-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,3-dioxolan-2-yl}acetateand2-hydroxyethyl{2-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,3-dioxolan-2-yl}acetate

Ethyl3-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-3-oxopropanoate(100 mg, 0.18 mmol) from step 1 was dissolved in 1,2-ethanediol (5 mL)followed by addition of methanesulfonic acid (0.001 mL, 0.02 mmol) andstirred at 30° C. for 5 h. The reaction was quenched by addition ofammonia (30 mL, 28% in water) and the resulting precipitate wascollected by vacuum filtration. The solid was dissolved in ethyl acetate(50 mL) and washed with water (2×20 mL). The organic layer was driedover solid sodium sulfate and concentrated under vacuum to give amixture of ethyl3-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-3-oxopropanoate,ethyl{2-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,3-dioxolan-2-yl}acetateand 2-hydroxyethyl{2-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,3-dioxolan-2-yl}acetate(112 mg) as pale yellow oil, which was used in the next step withoutfurther purification. UPLC-MS (Method G): R_(t)=0.89 min; m/z=560(M+H)⁺; R_(t)=0.92 min; m/z=604 (M+H)⁺; R_(t)=0.73 min; m/z=620 (M+H)⁺.

Step 3:{2-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)-phenyl]amino}-1H-benzimidazol-5-yl]-1,3-dioxolan-2-yl}aceticacid

A mixture of ethyl3-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-3-oxopropanoate,ethyl{2-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,3-dioxolan-2-yl}acetateand 2-hydroxyethyl{2-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,3-dioxolan-2-yl}acetate(112 mg) from step 2 were dissolved in a mixture of methanol (4 mL) andwater (1 mL). Sodium hydroxide (12 mg, 0.23 mmol) was added and thereaction was stirred at room temperature overnight. The methanol wasremoved by evaporation and the residual mixture was acidified withaqueous hydrochloric acid (1 M) and then extracted with ethyl acetate(3×50 mL). The combined organic layers were dried over solid sodiumsulfate and concentrated under vacuum to give the title compound (60 mg,58% yield over two steps) as a colourless solid which was used withoutfurther purification. UPLC-MS (Method F): R_(t)=0.89 min; m/z=574(M+H)⁺. ¹H-NMR (300 MHz, CDCl₃): δ [ppm]=0.57 (s, 6H), 0.90 (s, 6H),1.00-1.24 (m, 2H), 1.40-1.50 (d, 2H), 1.85 (t, 2H), 2.64 (s, 3H), 3.18(s, 2H), 3.78 (s, 2H), 4.14 (m, 1H), 6.98 (d, 2H), 7.12 (m, 3H), 8.14(s, 1H).

Step 4:N-hydroxy-2-{2-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,3-dioxolan-2-yl}acetamide

To a solution of 1,1′-carbonyldiimidazole (34 mg, 0.21 mmol) inN,N-dimethylformamide (5 mL),{2-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,3-dioxolan-2-yl}aceticacid (60 mg, 0.10 mmol) from step 3 was added. The resulting mixture wasstirred at 50° C. for 4 h. After the addition of hydroxylaminehydrochloride (15 mg, 0.21 mmol) the mixture was stirred at 50° C. for afurther 4 h. The reaction was then quenched by addition of water (20 mL)and extracted with ethyl acetate (3×50 mL). The combined organic layerswere dried over solid sodium sulfate and concentrated under vacuum togive intermediate 1-11 (68 mg, 51% ) as a colourless solid which wasused without further purification. LCMS (Method C): R_(t)=2.28 min;m/z=591 (M+H)⁺.

EXAMPLES Example 2-1 (±)5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine

150 mg (0.30 mmol) (±)5-Bromo-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine(intermediate 1-1), 85.2 mg (0.60 mmol)(3,5-dimethyl-1,2-oxazol-4-yl)boronic acid (commercially available,CAS-RN: 16114-47-9), 24.7 mg (0.03 mmol)1,1′-(bisdiphenylphosphino)ferrocenedichloropalladium(II) and 96.1 mg(0.91 mmol) Na₂CO₃ in 3.2 mL dioxane and 0.46 mL water (both solventshave been degassed) were heated in the microwave oven at 110° C. for 60min. The reaction mixture was given on a flash column and was washedwith ethyl acetate (250 mL) to remove the catalyst and the salts. Thefiltrate was evaporated to dryness and the residue was purified bycolumn chromatography to yield 103.1 mg (66.6% ) of the title compound.UPLC-MS: R_(t)=1.53 min; m/z=513.2 (ES+, M+1). ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm]=0.92-1.02 (m, 6H), 1.02-1.22 (m, 4H), 1.34-1.50 (m,2H), 1.72-1.97 (m, 3H), 2.07 (t, 1H), 2.22 (s, 3H), 2.41 (s, 3H), 4.68(t, 1H), 6.93-7.03 (m, 1H), 7.26-7.40 (m, 3H), 7.61 (d, 1H), 7.82 (d,2H), 9.07 (s, 1H).

Example 2-1-15-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine,enantiomer A

The racemic compound (±)5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)-phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine(example 2-1; 67 mg) was separated via chiral HPLC (system: Agilent Prep1200, 2×Prep Pump, DLA, MWD, Prep FC; column: Chiralpak IA, 5 μM 250×20mm; injection: 67 mg in 4×0.5 mL acetone/DMSO; solvent: hexane,2-propanol, diethylamine (70:30:0.1); flow: 25 mL/min; detection: UV 254nm) into its enantiomers yielding 20 mg of the title compound(enantiomer A, retention time range: 4.8-7.0 min) and 25 mg ofenantiomer B, described in example 2-1-2. ¹H-NMR (400 MHz, CDCl₃): δ[ppm]=0.90-1.02 (m, 6H), 1.02-1.17 (m, 4H), 1.34-1.52 (m, 2H), 1.72-1.96(m, 3H), 2.07 (t, 1H), 2.22 (s, 3H), 2.39 (s, 3H), 4.68 (t, 1H), 6.98(dd, 1H), 7.27-7.40 (m, 3H), 7.61 (d, 1H), 7.77-7.88 (m, 2H), 9.07 (s,1H).

Example 2-1-25-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine,enantiomer B

The racemic compound (±)5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)-phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine(example 2-1; 67 mg) was separated via chiral HPLC (system: Agilent Prep1200, 2×Prep Pump, DLA, MWD, Prep FC; column: Chiralpak IA, 5 μM 250×20mm; injection: 67 mg in 4×0.5 mL acetone/DMSO; solvent: hexane,2-propanol, diethylamine (70:30:0.1); flow: 25 mL/min; detection: UV 254nm) into its enantiomers yielding 25 mg of the title compound(enantiomer B, retention time range: 10.5-13.8 min) and 20 mg ofenantiomer A, described in example 2-1-1. ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]=0.89-1.02 (m, 6H), 1.02-1.19 (m, 4H), 1.32-1.54 (m, 2H), 1.70-1.97(m, 3H), 2.07 (t, 1H), 2.22 (s, 3H), 2.39 (s, 3H), 4.68 (br. s., 1H),6.98 (dd, 1H), 7.25-7.43 (m, 3H), 7.61 (d, 1H), 7.72-7.92 (m, 2H), 9.07(s, 1H).

Example 2-2 (±)3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzoicacid

100 mg (0.18 mmol) (±) Methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzoate(example 2-15) were dissolved in 0.8 mL dioxane. 8.7 mg (0.36 mml) LiOHand 0.26 mL water were added and the reaction mixture was stirred at 70°C. for 2.5 hours. The reaction mixture was evaporated to dryness and theresidue was suspended in water (10 mL). After acidification of themixture to pH 4 (1N HCl) the reaction mixture was stirred for two hoursat room temperature. The solid was filtered off, washed with water anddried overnight yielding 75.8 mg (73.9% ) of the title compound.UPLC-MS: R_(t)=1.37 min; m/z=538.2 (ES+, M+1). ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm]=0.88-1.18 (m, 10H), 1.38-1.56 (m, 2H), 1.72-1.98 (m,3H), 2.08 (t, 1H), 4.71 (br., 1H), 7.30-7.43 (m, 3H), 7.57 (t, 1H),7.63-7.73 (m, 2H), 7.82 (d, 2H), 7.85-7.98 (m, 2H), 8.17 (s, 1H), 9.32(br., 1H), 12.99 (br., 1H).

Example 2-3 (±)4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzoicacid

100 mg (0.18 mmol) (±) Methyl4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzoate(example 2-18) were dissolved in 0.8 mL dioxane. 8.7 mg (0.36 mml) LiOHand 0.26 mL water were added and the reaction mixture was stirred at 70°C. for 2.5 hours. The reaction mixture was evaporated to dryness and theresidue was suspended in water (10 mL). After acidification of themixture to pH 4 (1 N HCl) the reaction mixture was stirred for two hoursat room temperature. The solid was filtered off, washed with water anddried overnight yielding 80.5 mg (78.5% ) of the title compound.UPLC-MS: R_(t)=1.43 min; m/z=538.2 (ES+, M+1). ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm]=0.92-1.18 (m, 10H), 1.32-1.47 (m, 1H), 1.53 (d, 1H),1.70-2.02 (m, 3H), 2.09 (t, 1H), 4.77 (t, 1H), 7.23-7.44 (m, 2H), 7.47(d, 1H), 7.70 (s, 1H), 7.72-7.84 (m, 5H), 7.92-8.14 (m, 2H), 9.85 (br.1H), 12.87 (br., 1H).

The examples in Table 1 were prepared in an analogous manner to example2-1, by reacting the corresponding intermediates and the correpondingboronic acids and—where appropriate—separated into their enantiomers asdescribed.

TABLE 1 Example, (intermediate; boronic acid: CAS-RN) Structure/NameMethods/analytical data 2-4, (1-1, 1188405-87-9)

UPLC-MS: R_(t) = 1.29 min; m/z = 484.2 (ES+, M + 1). ¹H-NMR (400 MHz,DMSO- d₆): δ [ppm] = 0.93-1.01 (m, 6H), 1.01-1.24 (m, 4H), 1.31-1.49 (m,2H), 1.67-1.96 (m, 3H), 2.05 (t, 1H), 4.64 (t, 1H), 7.16- 7.36 (m, 3H)7.48 (d, 1H), 7.60-7.70 (m, 1H), 7.75- 7.95 (m, 3H), 8.09 (br., 1H),9.01 (s, 1H), 12.79 (br., 1H).

2-4-1

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak ID, 5 μM 250 × 30 mm; injection: 25 mg in 1 × 4 mLdichloromethane/ methanol (1:1); solvent: hexane/2-propanol/diethylamine (70:30:0.1); flow: 50 mL/min; detection: UV 254 nm; R_(t) =21.6-28.0 min. ¹H-NMR (300 MHz, DMSO- d₆): δ [ppm] = 0.91-1.01  

(m, 6H), 1.01-1.18 (m, 4H), 1.28-1.51 (m, 2H), 1.66-1.94 (m, 3H), 2.05(t, 1H), 4.64 (br., 1H), 7.19- 7.40 (m, 3H), 7.48 (d, 1H), 7.63 (d, 1H),7.82 (d, H), 7.75-8.19 (very br., 2H), 9.00 (s, 1H), 12.78 (br., 1H).2-4-2

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak ID, 5 μM 250 × 30 mm; injection: 25 mg in 1 × 4 mLdichloromethane/ methanol (1:1); solvent: hexane/2-propanol/diethylamine (70:30:0.1); flow: 50 mL/min; detection: UV 254 nm; R_(t) =28.0-34.1 min. ¹H-NMR (300 MHz, DMSO- d₆): δ [ppm] = 0.91-1.01  

(m, 6H), 1.01-1.18 (m, 4H), 1.28-1.51 (m, 2H), 1.68-1.97 (m, 3H), 2.05(t, 1H), 4.62 (br., 1H), 7.19- 7.40 (m, 3H), 7.48 (d, 1H), 7.63 (d, 1H),7.82 (d, H), 7.75-8.19 (very br., 2H), 9.00 (s, 1H), 12.78 (br., 1H).2-5, (1-1; 947533-31-5)

UPLC-MS: R_(t) = 1.31 min; m/z = 512.3 (ES+, M + 1). ¹H-NMR (300 MHz,DMSO- d₆): δ [ppm] = 0.90-1.02 (m, 6H), 1.02-1.17 (m, 4H), 1.42 (t, 2H),1.72- 1.95 (m, 3H), 2.00-2.22 (m, 7H), 4.66 (br. s., 1H), 6.92 (dd, 1H),7.19-7.37 (m, 3H), 7.54 (d, 1H), 7.81 (d, 2H), 9.03 (s, 1H), 12.20 (br.,1H).

2-5-1

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak ID, 5 μM 250 × 20 mm; injection: 45 mg in 3 × 0.5 mLdichloromethane/ methanol (1:1); solvent: hexane/2-propanol/diethylamine (70:30:0.1); flow: 20 mL/min; detection: UV 254 nm; R_(t) =4.5-5.4 min. ¹H-NMR (300 MHz, DMSO- d₆): δ [ppm] = 0.87-1.02  

(m, 6H), 1.02-1.17 (m, 4H), 1.42 (t, 2H), 1.73- 1.97 (m, 3H), 2.01-2.22(m, 7H), 4.66 (br., 1H), 6.92 (d, 1H), 7.19-7.37 (m, 3H), 7.54 (d, 1H),7.81 (d, 2H), 9.02 (s, 1H), 12.16 (br. s., 1H). 2-5-2

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak ID, 5 μM 250 × 20 mm; injection: 45 mg in 3 × 0.5 mLdichloromethane/ methanol (1:1); solvent: hexane/2-propanol/diethylamine (70:30:0.1); flow: 20 mL/min; detection: UV 254 nm; R_(t) =7.4-8.6 min. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.90-1.02  

(m, 6H), 1.02-1.20 (m, 4H), 1.33-1.51 (m, 2H), 1.73-1.94 (m, 3H), 2.01-2.13 (m, 1H), 2.18 (s, 6H), 4.66 (br., 1H), 6.92 (dd, 1H), 7.24 (d, 1H),7.31 (d, 2H), 7.54 (d, 1H), 7.76- 7.85 (m, 2H), 9.00 (s, 1H), 12.15 (br.s., 1H). 2-7 (1-1; 1009071-34-4)

UPLC-MS (method B): R_(t) = 1.55 min; m/z = 498.2 (ES+, M + 1). ¹H-NMR(400 MHz, DMSO- d₆): δ [ppm] = 0.86-1.01 (m, 6H), 1.01-1.20 (m, 4H),1.41 (t, 2H), 1.69- 1.96 (m, 3H), 1.97-2.14 (m, 1H), 2.33 (br., 3H),4.65 (t, 1H), 7.08 (d, 1H), 7.31 (d, 2H), 7.41 (s, 1H), 7.48-7.70 (m,2H), 7.81 (d, 2H), 9.01 (s, 1H), 12.52 (br., 1H).

2-8 (1-1; 1217500-54-3)

UPLC-MS R_(t) = 1.32 min; m/z = 484.2 (ES+, M + 1). ¹H-NMR (400 MHz,DMSO- d₆): δ [ppm] = 0.93-1.02 (m, 6H), 1.02-1.16 (m, 4H), 1.32-1.50 (m,2H), 1.68-1.97 (m, 3H), 2.08 (t, 1H), 4.66 (t, 1H), 6.65 (s, 1H),7.25-7.38 (m, 2H), 7.45-7.72 (m, 3H), 7.72- 7.89 (m, 3H), 9.05 (s, 1H),12.70 (br., 1H).

2-9 (1-1; 1008139-25-0)

UPLC-MS R_(t) = 1.43 min; m/z = 485.2 (ES+, M + 1). ¹H-NMR (400 MHz,DMSO- d₆): δ [ppm] = 0.91-1.01 (m, 6H), 1.01-1.18 (m, 4H), 1.32-1.49 (m,2H), 1.69-1.96 (m, 3H), 2.05 (t, 1H), 4.66 (t, 1H), 7.29- 7.40 (m, 3H),7.57 (d, 1H), 7.73-7.91 (m, 3H), 9.08 (s, 1H), 9.14 (s, 1H), 9.36 (s,1H).

2-10 (1-2; 947533-31-5)

UPLC-MS (method B): R_(t) = 1.66 min; m/z = 528.2 (ES+, M + 1). ¹H-NMR(400 MHz, DMSO- d₆): δ [ppm] = 0.92-1.01 (m, 6H), 1.01-1.28 (m, 4H),1.34-1.52 (m, 2H), 1.72-1.96 (m, 3H), 2.09 (t, 1H), 2.20 (br., s, 6H),4.67 (t, 1H), 6.96 (dd, 1H), 7.29 (d, 1H), 7.51-7.69 (m, 3H), 7.76-7.94(m, 2H), 9.25 (s, 1H), 12.19 (br., 1H).

2-10-1

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak IA, 5 μM 250 × 20 mm; injection: 22 mg in 2 × 0.5 mLdichloromethane/ methanol (1:1); solvent: hexane/ethanol/diethylamine(70:30:0.1); flow: 20 mL/min; detection: UV 254 nm; R_(t) = 2-2.98 min.¹H-NMR (300 MHz, DMSO- d₆): δ [ppm] = 0.91-1.31  

(m, 10H), 1.33-1.53 (m, 2H), 1.72-1.94 (m, 3H), 2.07 (t, 1H), 2.18 (s,6H), 4.67 (t, 1H), 6.95 (dd, 1H), 7.29 (d, 1H), 7.51-7.71 (m, 3H), 7.83(d, 2H), 9.26 (s, 1H), 12.19 (br. s., 1H). 2-10-2

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak IA, 5 μM 250 × 20 mm; injection: 22 mg in 2 × 0.5 mLdichloromethane/ methanol (1:1); solvent: hexane/ethanol/diethylamine(70:30:0.1); flow: 20 mL/min; detection: UV 254 nm; R_(t) = 5-5.73 min.¹H-NMR (300 MHz, DMSO- d₆): δ [ppm] = 0.88-1.27  

(m, 10H), 1.33-1.52 (m, 2H), 1.73-1.97 (m, 3H), 1.99-2.15 (m, 2H), 2.18(s, 6H), 2.26 (d, 1H), 4.67 (br., 1H), 6.95 (dd, 1H), 7.29 (d, 1H),7.53-7.70 (m, 3H), 7.83 (d, 2H), 9.26 (s, 1H), 12.19 (br. s., 1H). 2-11(1-1; 351422-73-6)

UPLC-MS: R_(t) = 1.29 min; m/z = 537.2 (ES+, M + 1). ¹H-NMR (300 MHz,DMSO- d₆): δ [ppm] = 0.86-1.02 (m, 6H), 1.02-1.22 (m, 4H), 1.33-1.50 (m,2H), 1.70-1.95 (m, 3H), 2.08 (t, 1H), 4.69 (br. s., 1H), 7.26-7.45 (m,4H), 7.45- 7.58 (m, 1H), 7.63 (d, 1H), 7.73-7.91 (m, 5H), 8.04- 8.23 (m,2H), 9.11 (s, 1H).

2-12 (1-1; 847818-68-2)

UPLC-MS: R_(t) = 1.48 min; m/z = 512.3 (ES+, M + 1). ¹H-NMR (300 MHz,DMSO- d₆): δ [ppm] = 0.97-0.99 (m, 6H), 1.06-1.15 (m, 4H), 1.43 (t, 2H),1.73- 1.91 (m, 3H), 2.08 (t, 1H), 2.16 (s, 3H), 3.76 (s, 3H), 4.65-4.74(m, 1H), 6.11 (s, 1H), 7.11 (dd, 1H), 7.32-7.35 (m, 2H), 7.47 (d, 1H),7.64 (d, 1H), 7.81- 7.86 (m, 2H), 9.13 (s, 1H).

2-12-1

System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Gilson: LiquidHandler 215; column: Chiralpak ID 5 μM 250 × 30 mm; solvent: hexane/2-propanol/diethylamine (70:30:0.1); flow: 50 mL/min; temperature: RT;solution: 32 mg/1.6 mL DCM/MeOH; injection: 2 × 0.8 mL; detection: UV254 nm; R_(t) = 11.5-13.5 min.

2-12-2

System: Agilent: Prep 1200, 2xPrep Pump, DLA, MWD, Gilson: LiquidHandler 215; column: Chiralpak ID 5 μM 250 × 30 mm; solvent: hexane/2-propanol/diethylamine (70:30:0.1); flow: 50 mL/min; temperature: RT;solution: 32 mg/1.6 mL DCM/MeOH; injection: 2 × 0.8 mL; detection: UV254 nm; R_(t) = 23.4-27.2 min.

2-13 (1-1; 847818-55-7)

UPLC-MS: R_(t) = 1.28 min; m/z = 498.2 (ES+, M + 1). ¹H-NMR (400 MHz,DMSO- d₆): δ [ppm] = 0.90-1.16 (m, 10H), 1.33-1.49 (m, 2H), 1.67-1.96(m, 3H), 2.04 (t, 1H), 3.85 (s, 3H), 4.63 (t, 1H), 7.20 (dd, 1H), 7.31(d, 2H), 7.48 (d, 1H), 7.58 (d, 1H), 7.73-7.89 (m, 3H), 8.03 (s, 1H),9.01 (s, 1H).

2-13-1

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak ID, 5 μM 250 × 30 mm; injection: 50 mg in 2 × 1 mLdichloromethane; solvent: hexane/ethanol/ diethylamine (70:30:0.1);flow: 50 mL/min; detection: UV 254 nm; R_(t) = 7.3-8.5 min. ¹H-NMR (300MHz, DMSO- d₆): δ [ppm] = 0.90-1.17 (m, 10H), 1.32-1.48 (m,  

2H), 1.69-1.96 (m, 3H), 2.04 (t, 1H), 3.85 (s, 3H), 4.64 (br., 1H), 7.20(dd, 1H), 7.31 (d, 2H), 7.49 (d, 1H), 7.58 (d, 1H), 7.75- 7.88 (m, 3H),8.04 (s, 1H), 9.02 (s, 1H). 2-13-2

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak ID, 5 μM 250 × 30 mm; injection: 50 mg in 2 × 1 mLdichloromethane; solvent: hexane/ethanol/ diethylamine (70:30:0.1);flow: 50 mL/min; detection: UV 254 nm; R_(t) = 8.7-10.9 min. ¹H-NMR (300MHz, DMSO- d₆): δ [ppm] = 0.89-1.18 (m, 10H), 1.31-1.48 (m,  

2H), 1.69-1.97 (m, 3H), 2.04 (t, 1H), 3.85 (s, 3H), 4.55-4.71 (m, 1H),7.20 (dd, 1H), 7.31 (d, 2H), 7.49 (d, 1H), 7.55-7.61 (m, 1H), 7.75-7.88(m, 3H), 8.04 (s, 1H), 9.02 (s, 1H). 2-14 (1-1; 762262-09-9)

UPLC-MS: R_(t) = 1.58 min; m/z = 525.2 (ES+, M + 1). ¹H-NMR (400 MHz,DMSO- d₆): δ [ppm] = 0.93-1.02 (m, 6H), 1.02-1.22 (m, 4H), 1.42 (t, 2H),1.70- 1.97 (m, 3H), 2.09 (t, 1H), 3.88 (s, 3H), 4.68 (t, 1H), 7.08 (s,1H), 7.23-7.38 (m, 3H), 7.42 (dd, 1H), 7.64 (d, 1H), 7.77-7.88 (m, 3H),8.09-8.22 (m, 1H), 9.11 (s, 1H).

2-15 (1-1; 99769-19-4)

UPLC-MS: R_(t) = 1.62 min; m/z = 552.2 (ES+, M + 1). ¹H-NMR (400 MHz,DMSO- d₆): δ [ppm] = 0.90-1.02 (m, 6H), 1.02-1.20 (m, 4H), 1.36-1.51 (m,2H), 1.72-1.95 (m, 3H), 2.08 (t, 1H), 3.89 (s, 3H), 4.69 (br., 1H),7.26-7.41 (m, 3H), 7.55-7.71 (m, 3H), 7.80-7.99 (m, 4H), 8.19 (s, 1H),9.10 (s, 1H).

2-16 (1-1; 1138450-30-2)

UPLC-MS: R_(t) = 1.49 min; m/z = 566.2 (ES+, M + 1). ¹H-NMR (300 MHz,DMSO- d₆): δ [ppm] = 0.89-1.20 (m, 10H), 1.33-1.52 (m, 2H), 1.68-1.93(m, 3H), 2.07 (t, 1H), 3.95 (s, 3H), 4.67 (br., 1H), 7.00-7.09 (m, 1H),7.27-7.43 (m, 3H), 7.59 (d, 1H), 7.82 (d, 2H), 8.07 (s, 1H), 9.08 (s,1H).

2-16-1

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak IA, 5 μM 250 × 20 mm; injection: 50 mg in 3 × 0.5 mLdichloromethane/ methanol (1:1); solvent: hexane/isopropanol/diethylamine (70:30:0.1); flow: 20 mL/min; detection: UV 254 nm; R_(t) =5.7-6.9 min. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.91-1.01 (m, 6H),1.01-1.16 (m,  

4H), 1.32-1.48 (m, 2H), 1.73-1.93 (m, 3H), 2.07 (t, 1H), 3.95 (s, 3H),4.66 (br., 1H), 7.04 (dd, 1H), 7.32 (d, 2H), 7.38 (d, 1H), 7.59 (d, 1H),7.78-7.85 (m, 2H), 8.07 (s, 1H), 9.06 (s, 1H). 2-16-2

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak IA, 5 μM 250 × 20 mm; injection: 50 mg in 3 × 0.5 mLdichloromethane/ methanol (1:1); solvent: hexane/isopropanol/diethylamine (70:30:0.1); flow: 20 mL/min; detection: UV 254 nm; R_(t) =9.7-11.5 min. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.91-1.01  

(m, 6H), 1.01-1.17 (m, 4H), 1.35-1.49 (m, 2H), 1.70-1.94 (m, 3H), 2.07(t, 1H), 3.95 (s, 3H), 4.66 (t, 1H), 7.00-7.08 (m, 1H), 7.32 (d, 2H),7.36- 7.40 (m, 1H), 7.59 (d, 1H), 7.76-7.85 (m, 2H), 8.07 (s, 1H), 9.06(s, 1H). 2-17 (1-1; 123088-59-5)

 

UPLC-MS: R_(t) = 1.32 min; m/z = 537.2 (ES+, M + 1). ¹H-NMR (300 MHz,DMSO- d₆): δ [ppm] = 0.88-1.19 (m, 10H), 1.32-1.52 (m, 2H), 1.70-1.98(m, 3H), 2.08 (t, 1H), 4.68 (br., 1H), 7.27-7.43 (m, 4H), 7.63 (d, 1H),7.70-7.80 (m, 3H), 7.86 (d, 2H), 7.90- 8.07 (m, 3H), 9.11 (s, 1H). 2-18(1-1; 99768-12-4)

 

UPLC-MS: R_(t) = 1.60 min; m/z = 552.2 (ES+, M + 1). ¹H-NMR (400 MHz,DMSO- d₆): δ [ppm] = 0.86-1.01 (m, 6H), 1.01-1.22 (m, 4H), 1.33-1.52 (m,2H), 1.72-1.96 (m, 3H), 2.07 (t, 1H), 3.86 (s, 3H), 4.68 (br., 1H),7.27-7.43 (m, 3H), 7.64 (d, 1H), 7.70- 7.91 (m, 5H), 7.93-8.09 (m, 2H),9.10 (s, 1H). 2-19 (1-1; 847818-62-6)

 

UPLC-MS: R_(t) = 1.31 min; m/z = 526.3 (ES+, M + 1). ¹H-NMR (400 MHz,DMSO- d₆): δ [ppm] = 0.93-1.18 (m, 10H), 1.32-1.50 (m, 2H), 1.70-1.98(m, 3H), 2.00-2.16 (m, 4H), 2.20 (s, 3H), 3.70 (s, 3H), 4.66 (t, 1H),6.82-6.93 (m, 1H), 7.21 (d, 1H), 7.28- 7.38 (m, 2H), 7.49-7.61 (m, 1H),7.78-7.88 (m, 2H), 9.02 (s, 1H). 2-20 (1-1; 720702-41-0)

 

UPLC-MS: R_(t) = 1.44 min; m/z = 498.2 (ES+, M + 1). ¹H-NMR (300 MHz,DMSO- d₆): δ [ppm] = 0.90-1.22 (m, 10H), 1.27-1.51 (m, 2H), 1.72-1.99(m, 3H), 2.08 (t, 1H), 3.85 (s, 3H), 4.61-4.78 (m, 1H), 7.13 (dd, 1H),7.33 (d, 2H), 7.45 (d, 1H), 7.52 (d, 1H), 7.64 (d, 1H), 7.83 (d, 2H),9.12 (s, 1H). 2-21 (1-2; 16114-47-9)

 

UPLC-MS: R_(t) = 1.68 min; m/z = 529.2 (ES+, M + 1). ¹H-NMR (400 MHz,DMSO- d₆): δ [ppm] = 0.90-1.18 (m, 10H), 1.36-1.51 (m, 2H), 1.70-1.97(m, 3H), 2.07 (t, 1H), 2.21 (s, 3H), 2.40 (s, 3H), 4.69 (t, 1H), 7.02(dd, 1H), 7.41 (d, 1H), 7.59-7.71 (m, 3H), 7.85 (d, 2H), 9.30 (s, 1H).2-21-1

 

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak IA, 5 μM 250 × 20 mm; injection: 55 mg in 3 × 0.5 mLdichloromethane/ methanol (1:1); solvent: hexane/ethanol/ diethylamine(70:30:0.1); flow: 20 mL/min; detection: UV 254 nm; R_(t) = 10.0-11.9min. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.91-1.01 (m, 6H), 1.01-1.20(m, 4H), 1.35-1.50 (m, 2H), 1.75-1.94 (m, 3H), 2.07 (t, 1H), 2.22 (s,3H), 2.39 (s, 3H), 4.69 (br., 1H), 7.02 (dd, 1H), 7.41 (d, 1H),7.60-7.70 (m, 3H), 7.85 (d, 2H), 9.30 (s, 1H). 2-21-2

 

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak IA, 5 μM 250 × 20 mm; injection: 55 mg in 3 × 0.5 mLdichloromethane/ methanol (1:1); solvent: hexane/ethanol/ diethylamine(70:30:0.1); flow: 20 mL/min; detection: UV 254 nm; R_(t) = 25.4-28.4min. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.90-1.20 (m, 10H), 1.34-1.53(m, 2H), 1.75-1.94 (m, 3H), 2.00-2.13 (m, 1H), 2.22 (s, 3H), 2.39 (s,3H), 4.69 (br., 1H), 7.02 (dd, 1H), 7.41 (d, 1H), 7.60-7.70 (m, 3H),7.85 (d, 2H), 9.31 (s, 1H). 2-22 (1-2; 1217500-54-3)

 

UPLC-MS (method B): R_(t) = 1.63 min; m/z = 500.2 (ES+, M + 1). ¹H-NMR(400 MHz, DMSO- d₆): δ [ppm] = 0.89-1.20 (m, 10H), 1.36-1.52 (m, 2H),1.70-1.97 (m, 3H), 2.06 (t, 1H), 4.66 (br., 1H), 6.61-6.73 (m, 1H),7.48- 7.73 (m, 5H), 7.78-7.92 (m, 3H), 9.28 (s, 1H), 12.7 (very br.,1H). 2-23 (1-3; 16114-47-9)

 

UPLC-MS: R_(t) = 1.59 min; m/z = 497.2 (ES+, M + 1). ¹H-NMR (400 MHz,DMSO- d₆): δ [ppm] = 0.93-1.17 (m, 10H), 1.29-1.52 (m, 2H), 1.73-1.96(m, 3H), 2.08 (t, 1H), 2.22 (s, 3H), 2.39 (s, 3H), 4.71 (t, 1H), 7.02(dd, 1H), 7.42 (d, 1H), 7.60-7.72 (m, 3H), 7.92 (d, 2H), 9.32 (s, 1H).2-23-1

 

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak IA, 5 μM 250 × 20 mm; injection: 65 mg in 3 × 0.5 mLdichloromethane/ methanol (1:1); solvent: hexane/ethanol/ diethylamine(70:30:0.1); flow: 20 mL/min; detection: UV 254 nm; R_(t) = 10.1-12.5min. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.93-1.02 (m, 6H), 1.02-1.15(m, 4H), 1.35-1.51 (m, 2H), 1.75-1.95 (m, 3H), 2.08 (t, 1H), 2.22 (s,3H), 2.39 (s, 3H), 4.71 (br., 1H), 7.02 (dd, 1H), 7.42 (d, 1H), 7.66(dd, 3H), 7.92 (d, 2H), 9.32 (s, 1H). 2-23-2

 

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak IA, 5 μM 250 × 20 mm; injection: 65 mg in 3 × 0.5 mLdichloromethane/ methanol (1:1); solvent: hexane/ethanol/ diethylamine(70:30:0.1); flow: 20 mL/min; detection: UV 254 nm; R_(t) = 21.4-26.4min. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.90-1.02 (m, 6H), 1.02-1.16(m, 4H), 1.35-1.51 (m, 2H), 1.73-1.94 (m, 3H), 2.08 (t, 1H), 2.22 (s,3H), 2.39 (s, 3H), 4.71 (t, 1H), 7.02 (dd, 1H), 7.42 (d, 1H), 7.66 (dd,3H), 7.92 (d, 2H), 9.32 (s, 1H). 2-24 (1-3; 947533-31-5)

 

UPLC-MS (method B): R_(t) = 1.55 min; m/z = 496.3 (ES+, M + 1). ¹H-NMR(400 MHz, DMSO- d₆): δ [ppm] = 0.87-1.20 (m, 10H), 1.32-1.52 (m, 2H),1.71-1.98 (m, 3H), 2.08 (t, 1H), 2.19 (br., 6H), 4.68 (t, 1H), 6.95 (dd,1H), 7.29 (d, 1H), 7.52-7.72 (m, 3H), 7.85-7.95 (m, 2H), 9.26 (s, 1H),12.18 (s, 1H). 2-24-1

 

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak IA, 5 μM 250 × 20 mm; injection: 33 mg in 2 × 0.5 mLdichloromethane/ methanol (1:1); solvent: hexane/ethanol/ diethylamine(70:30:0.1); flow: 20 mL/min; detection: UV 254 nm; R_(t) = 7.0-8.1 min.¹H-NMR (300 MHz, DMSO- d₆): δ [ppm] = 0.89-1.18 (m, 10H), 1.33-1.52 (m,2H), 1.74-1.98 (m, 3H), 2.08 (t, 1H), 2.18 (br., 6H), 4.68 (br., 1H),6.95 (dd, 1H), 7.28 (d, 1H), 7.52- 7.70 (m, 3H), 7.89 (d, 2H), 9.28(very br., 1H), 12.19 (very br., 1H). 2-24-2

 

System: Agilent Prep 1200, 2xPrep Pump, DLA, MWD, Prep FC; column:Chiralpak IA, 5 μM 250 × 20 mm; injection: 33 mg in 2 × 0.5 mLdichloromethane/ methanol (1:1); solvent: hexane/ethanol/ diethylamine(70:30:0.1); flow: 20 mL/min; detection: UV 254 nm; R_(t) = 12.2-14.5min. ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.89-1.01 (m, 6H), 1.01-1.29(m, 4H), 1.33-1.53 (m, 2H), 1.73-1.96 (m, 3H), 2.08 (t, 1H), 2.18 (br.,6H), 4.69 (br., 1H), 6.95 (dd, 1H), 7.28 (d, 1H), 7.57 (d, 1H), 7.65 (d,2H), 7.89 (d, 2H), 9.26 (very br., 1H), 12.18 (very br., 1H).

Example 2-255-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-(3,3,5,5-tetramethylcyclohexyl)-N-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-amine

A solution ofN′-acetyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)-phenyl]amino}-1H-benzimidazole-5-carbohydrazide(330 mg) (Intermediate 1-6) in phosphoryl chloride (5.0 mL) was stirredat 110° C. for 10 h. After removal of phosphoryl chloride, 10% aqueousNaOH was added (pH 12) followed by extraction with ethyl acetate. Thecombined organic phases were dried over sodium sulfate. The sovent wasremoved in vacuo followed by chromatography of the crude product. Thedesired compound was obtained in 10% yields (over 3 steps, 12 mg). ESI+:514 [M+1] ¹H-NMR (DMSO-d₆): δ [ppm]=0.98 (s, 6H), 1.13 (s, 6H),1.23-1.42 (m, 2H), 1.55-1.66 (m, 2H), 1.99-2.13 (m, 2H), 2.57 (s, 3H),4.58-4.76 (m, 1H), 7.34 (d, 2H), 7.65 (dd, 1H), 7.71 (d, 2H), 7.82 (d,1H), 7.90 (d, 1H), 9.16 (br, 1H).

Example 2-265-(5-Methyl-1,2,4-oxadiazol-3-yl)-1-(3,3,5,5-tetramethylcyclohexyl)-N-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-amine

To a solution of5-N′-hydroxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazole-5-carboximidamide(245 mg) (Intermediate 1-7) in toluene (5.0 mL) were added acetylchloride (33 μL, 0.45 mmol) and NEt₃ (75 μL, 0.54 mmol). The mixture wasstirred at 125° C. for 10 h. After removal of the solvent and subsequentpurification by chromatography the desired compound was obtained in 18%yield (32 mg, over 3 steps). ESI+: 514 [M+1] ¹H-NMR (DMSO-d₆): δ[ppm]=0.98 (s, 6H), 1.12 (s, 6H), 1.1-20-1.40 (m, 2H), 1.57-1.60 (m,2H), 2.02-2.12 (m, 2H), 2.65 (s, 3H), 4.55-4.79 (m, 1H), 7.33 (d, 2H),7.63-7.83 (m, 4H), 7.94 (d, 1H), 9.12 (s, 1H).

Example 2-27 (±)5-(1H-tetrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(trans)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine

50 mg (0.11 mmol) (±)2-{[4-(Trifluoromethoxy)phenyl]amino}-1-[(trans)-3,3,5-trimethylcyclohexyl]-1H-benzimidazole-5-carbonitrile(intermediate 1-8) and 6 mg (0.09 mmol) iron(III) acetate were dissolvedin N,N-dimethylformamide (4.5 mL) and methanol (0.5 mL). Finally 42 mg(0.36 mmol) trimethylsilylazide was added. Nitrogen was passed throughthe mixture for 10 minutes; the vial was sealed and heated to 90° C. for60 h. To the mixture was added water and it was subjected to extractionwith ethyl acetate. The organic phases were dried with sodiumsulfate,the solvent was evaporated and purified by HPLC-colum chromatography,yielding 32 mg (55% ) of the desired product. ¹H-NMR (400 MHz, DMSO-d₆):δ [ppm]=0.99 (s, 3 H), 1.10 (s, 3H), 1.12 (d, 3H), 1.21-1.31 (m, 2H),1.42-1.55 (m, 2H), 1.65 (br. m, 1H), 2.23-2.41 (m, 2H), 4.74 (br. m,1H), 7.34 (m, 2H), 7.72-7.80 (m, 4H), 8.01 (s, 1H), 9.14 (s, 1H).UPLC-MS (Method A): R_(t)=1.34 min; MS (ES+, M+1) 486.2; MS (ES−, M−1)484.2.

Example 2-281-(3,3,5,5-tetramethylcyclohexyl)-5-(1H-tetrazol-5-yl)-N-[4-(trifluoromethoxy)-phenyl]-1H-benzimidazol-2-amine

100 mg (0.22 mmol)1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)-phenyl]amino}-1H-benzimidazole-5-carbonitrile(Intermediate 1-7, step 1), and 12 mg (0.09 mmol) iron(III) acetate weredissolved in N,N-dimethylformamide (8 mL) and methanol (1 mL). Finally83 mg (0.72 mmol) trimethylsilylazide were added. Nitrogen was passedthrough the mixture for 10 minutes, the vial was sealed and heated to 80° C. for 15 h. Due to low conversion, further iron(III) acetate (0.4 eq)and trimethylsilylazide (6 eq.) were added. The mixture was stirred at90° C. for 67 h. Silica gel was added and the solvent was removed. Theresidue was directly submitted to flash chromatography with a silica gelcartridge (biotage, KP-SIL, dichloromethane/methanol gradient). Furtherpurification by HPLC-colum chromatography followed, yielding 55 mg (50%) of the desired product. ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.98 (s, 6H), 1.13 (s, 6 H), 1.23-1.41 (m, 2 H), 1.54-1.64 (m, 2 H), 2.08 (t, 2H), 4.68 (br. m, 1 H), 7.31-7.39 (m, 2 H), 7.68-7.76 (m, 3 H), 7.80-7.86(m, 1 H), 8.01 (s, 1H), 9.16 (s, 1 H). UPLC-MS (Method A): R_(t)=1.38min; MS (ES+, M+1) 500.3; MS (ES−, M−1) 498.3.

Example 2-295-(3,5-dimethyl-1H-pyrazol-4-yl)-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-N-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-amine

A suspension of5-bromo-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-N-[4-(trifluoro-methoxy)phenyl]-1H-benzimidazol-2-amine(intermediate 1-4; 100 mg, 0.19 mmol), sodium carbonate (60 mg, 0.5mmol) and3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(CAS No. [857530-80-4]; 84 mg, 0.38 mmol) in 1,4-dioxane (1 mL) andwater (0.25 mL) was degassed using argon in a microwave tube for 10 min.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14 mg, 0.02mmol) was added and the tube sealed. The reaction was heated bymicrowave irradiation for 5 h at 140° C. The reaction was diluted withethyl acetate (10 mL) and water (10 mL). The layers were separated andthe aqueous layer was extracted with ethyl acetate (2×10 mL). Thecombined organics were dried over sodium sulfate and concentrated undervacuum. The crude material was purified by reverse phase chromatography(BIOTAGE SP4, 30 g Biotage cartridge) using acetonitrile and watercontaining 10 mM ammonium bicarbonate pH 10 buffer (3:97 to 100:0) togive the title compound (5.6 mg, 5.4% ) as a pale purple solid. UPLC-MS(Method H): R_(t)=3.36 min; m/z=540 (M+H)⁺. ¹H-NMR (300 MHz, DMSO-d₆): δ[ppm]=0.96 (s, 6H), 1.07 (s, 6H), 1.20-1.30 (m, 2H), 1.52 (d, 2H), 1.94(br. s, 6H), 2.06 (t, 2H), 2.09 (s, 3H), 4.50 (m, 1H), 7.02 (s, 1H),7.26 (d, 2H), 7.45 (s, 1H), 7.56 (d, 2H), 8.87 (s, 1H).

Example 2-306-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(3,3,5,5-tetramethylcyclohexyl)-N-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-amine

To a solution ofN-[(1E)-1-(dimethylamino)ethylidene]-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxamide(intermediate 1-5; 50 mg, 0.09 mmol) in acetic acid (1 mL), hydrazinehydrate (0.015 mL, 0.31 mmol) was added and the reaction was heated to90° C. for 30 min. The reaction was cooled, saturated sodium bicarbonatesolution (20 mL) was added and the mixture was extracted with ethylacetate (2×20 mL). The combined organics were dried over solid magnesiumsulfate, filtered and concentrated under vacuum. The crude material waspurified by flash silica column chromatography (dichloromethane) to givethe title compound (19 mg, 39% ) as a colourless solid. UPLC-MS (MethodG): R_(t)=0.60 min; m/z=527 (M+H)⁺. ¹H-NMR (300 MHz, CDCl₃): δ[ppm]=0.73 (s, 6H), 0.96 (s, 6 H), 1.20-1.41 (m, 2H), 1.50-1.70 (m, 2H),1.95 (t, 2H), 2.54 (s, 3H), 2.87 (s, 3H), 4.45 (m, 1H), 7.04 (d, 2H),7.19 (d, 2H), 7.25 (s, 1H), 7.41 (s, 1H), 8.23 (s, 1H).

Example 2-31 (±)5-(5-methyl-1,3,4-oxadiazol-2-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine

200 mg (0.37 mmol)5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine(Intermediate 1-9), 60 mg (0.37 mmol) 2-bromo-5-methyl-1,3,4-oxadiazole(commercially available, CAS-RN: 864750-58-3), 30 mg (0.04 mmol)1,1′-(bisdiphenylphosphino)ferrocenedichloropalladium(II) and 117 mg(1.1 mmol) sodium carbonate in 3.9 mL dioxane (degassed) and 0.55 mLwater (degassed) were heated at 110° C. for 90 min in a microwave oven.Due to an incomplete reaction additional 20 mg catalyst were added andheating was continued at 110° C. for two hours. The reaction mixture wascooled and eluted with ethyl acetate (250 mL) via a FLAS column (20 g).After evaporation of the solvent the residue was purified by HPLCyielding 27.8 mg (14.4% ) of the title compound. UPLC-MS: R_(t)=1.46min; m/z=500.2 (M+1). ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.90-1.18 (m,10H), 1.31-1.52 (m, 2H), 1.68-1.99 (m, 3H), 2.08 (t, 1H), 2.58 (s, 3H),4.70 (br., 1H), 7.28-7.41 (m, 2H), 7.65 (d, 1H), 7.75 (d, 1H), 7.78-7.92(m, 3H), 9.21 (s, 1H).

Example 2-32 (±)5-(3,5-difluoro-4-methoxyphenyl)-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine

200 mg (0.37 mmol)5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine(Intermediate 1-9) 82.1 mg (0.37 mmol)5-bromo-1,3-difluoro-2-methoxybenzene (commercially available, CAS-RN:104197-14-0), 30 mg (0.04 mmol)1,1′-(bisdiphenylphosphino)ferrocenedichloropalladium(II) and 117 mg(1.1 mmol) sodium carbonate in 3.9 mL dioxane (degassed) and 0.55 mLwater (degassed) were heated at 110° C. for 90 min in a microwave oven.The reaction mixture was cooled and eluted with ethyl acetate (250 mL)via a FLAS column (20 g). After evaporation of the solvent the residuewas purified by HPLC yielding 81.8 mg (37.7% ) of the title compound.UPLC-MS: R_(t)=1.68 min; m/z=560.2 (M+1). ¹H-NMR (300 MHz, DMSO-d₆): δ[ppm]=0.90-1.18 (m, 10H), 1.32-1.52 (m, 2H), 1.68-2.00 (m, 3H), 2.06 (t,1H), 3.93 (s, 3H), 4.67 (br., 1H), 7.29-7.40 (m, 3H), 7.41-7.53 (m, 2H),7.60 (d, 1H), 7.72 (d, 1H), 7.84 (d, 2H), 9.11 (s, 1H).

Example 2-33 (±)2,6-difluoro-4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)phenol

200 mg (0.37 mmol)5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine(Intermediate 1-9), 76.9 mg (0.37 mmol) 4-bromo-2,6-difluorophenol(commercially available, CAS-RN: 104197-13-9), 30 mg (0.04 mmol)1,1′-(bisdiphenylphosphino)ferrocenedichloropalladium(II) and 117 mg(1.1 mmol) sodium carbonate in 3.9 mL dioxane (degassed) and 0.55 mLwater (degassed) were heated at 110° C. for 90 min in a microwave oven.The reaction mixture was cooled and eluted with ethyl acetate (250 mL)via a FLAS column (20 g). After evaporation of the solvent the residuewas purified by HPLC yielding 30.5 mg (14.4% ) of the title compound.UPLC-MS: R_(t)=1.44 min; m/z=546.2 (M+1). ¹H-NMR (300 MHz, DMSO-d₆): δ[ppm]=0.90-1.18 (m, 10H), 1.32-1.50 (m, 2H), 1.68-1.99 (m, 3H), 2.05 (t,1H), 4.66 (br., 1H), 7.22-7.45 (m, 5H), 7.56 (d, 1H), 7.65 (d, 1H), 7.83(d, 2H), 9.08 (s, 1H), 10.03 (br., 1H).

Example 2-34 (±)2,6-dimethyl-4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)phenol

200 mg (0.37 mmol)5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine(Intermediate 1-9) 74 mg (0.37 mmol) 4-bromo-2,6-dimethylphenol(commercially available, CAS-RN: 2374-05-2), 30 mg (0.04 mmol)1,1′-(bisdiphenylphosphino)ferrocenedichloropalladium(II) and 117 mg(1.1 mmol) sodium carbonate in 3.9 mL dioxane (degassed) and 0.55 mLwater (degassed) were heated at 110° C. for 90 min in a microwave oven.The reaction mixture was cooled and eluted with ethyl acetate (250 mL)via a FLAS column (20 g). After evaporation of the solvent the residuewas purified by HPLC yielding 7 mg (3% ) of the desired compound.UPLC-MS (method B): R_(t)=1.68 min; m/z=538.3 (M+1). ¹H-NMR (300 MHz,DMSO-d₆): δ [ppm]=0.89-1.25 (m, 10H), 1.40 (d, 1H), 1.59 (d, 1H),1.70-2.01 (m, 3H), 2.10 (t, 1H), 2.20 (s, 6H), 4.69 (br., 1H), 7.18 (s,2H), 7.38 (d, 1H), 7.42-7.58 (m, 3H), 7.60-7.84 (m, 3H), 8.32 (br., 1H),10.1 (very br., 1H).

Example 2-35 (±)5-(3-ethoxy-5-methyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine

200 mg (0.37 mmol)5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine(Intermediate 1-9) 75.8 mg (0.37 mmol)4-bromo-3-ethoxy-5-methyl-1,2-oxazole (commercially available, CAS-RN:169310-98-9), 30 mg (0.04 mmol)1,1′-(bisdiphenylphosphino)ferrocenedichloropalladium(II) and 117 mg(1.1 mmol) sodium carbonate in 3.9 mL dioxane (degassed) and 0.55 mLwater (degassed) were heated at 110° C. for 90 min in a microwave oven.The reaction mixture was cooled and eluted with ethyl acetate (250 mL)via a FLAS column (20 g). After evaporation of the solvent the residuewas purified by HPLC yielding 89.1 mg (37.9% ) of the title compound.UPLC-MS: R_(t)=1.32 min; m/z=543.3 (M+1). ¹H-NMR (300 MHz, DMSO-d₆): δ[ppm]=0.88-1.18 (m, 10H), 1.20 (t, 3H), 1.33-1.49 (m, 2H), 1.69-1.98 (m,3H), 2.07 (t, 1H), 2.41 (s, 3H), 3.87 (q, 2H), 4.66 (br., 1H), 7.21 (dd,1H), 7.26-7.39 (m, 2H), 7.52 (d, 1H), 7.59 (d, 1H), 7.78-7.89 (m, 2H),9.09 (s, 1H).

Example 2-365-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,3-oxazolidine-2,4-dione

To a solution of ethyl[5-(2,4-dioxo-1,3-oxazolidin-5-yl)-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-2-yl][4-(trifluoromethoxy)phenyl]carbamate(intermediate 1-10; 42 mg, 0.07 mmol) in methanol (5 mL) and water (1mL), sodium hydroxide (6 mg, 0.14 mmol) was added. The reaction mixturewas stirred at room temperature for 18 h then quenched by addition ofaqueous hydrochloric acid (10 mL, 1 M) and extracted with ethyl acetate(3×25 mL). The combined organic layers were dried over solid sodiumsulfate and concentrated under vacuum. The crude material was purifiedby triturating with dichloromethane to give the title compound (36 mg,97% ) as a colourless solid. UPLC-MS (Method F): R_(t)=0.75 min; m/z=545(M+H)⁺. ¹H-NMR (300 MHz, Methanol-d₄): δ [ppm]=0.86 (s, 6H), 1.07 (s,6H), 1.34 (s, 2H), 1.62 (d, 2H), 2.10 (t, 2H), 2.53 (s, 3H), 4.64 (m,1H), 6.21 (s, 1H), 7.15-7.33 (m, 5H), 7.44 (s, 1H).

Example 2-375-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,2-oxazol-3-ol

N-Hydroxy-2-{2-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,3-dioxolan-2-yl}acetamide(intermediate 1-11; 78 mg, 0.04 mmol, 33% purity) was dissolved inhydrochloric acid (3 mL, 9.90 mmol, 3.3 M in methanol) and stirred at70° C. for 5 h. The solvent was removed by evaporation and the residuewas dissolved in dichloromethane (20 mL) and saturated sodiumbicarbonate solution (20 mL). The layers were separated and the aqueouslayer was extracted with dichloromethane (2×20 mL). The combined organiclayers were dried over solid sodium sulfate and concentrated undervacuum. The material was purified by reverse phase chromatography(BIOTAGE SP4, 30 g Biotage cartridge) using acetonitrile and watercontaining 10 mM ammonium bicarbonate at pH 10 buffer (10:90 to 100:0)to give the title compound (20 mg, 43% ) as a colourless solid. UPLC-MS(Method F): R_(t)=0.79; m/z=529 (M+H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]=0.95 (s, 6H), 1.07 (s, 6H), 1.20-1.42 (m, 2H), 1.45-1.56 (m, 2H),2.04 (t, 2H), 2.49 (s, 2H), 4.58 (m, 1H), 6.19 (s, 1H), 7.29 (d, 2H),7.52 (s, 1H), 7.60-7.70 (m, 3H), 9.02 (br s, 1H).

Further, the compounds of formula (I) of the present invention can beconverted to any salt as described herein, by any method which is knownto the person skilled in the art. Similarly, any salt of a compound offormula (I) of the present invention can be converted into the freecompound, by any method which is known to the person skilled in the art.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilised to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike. For oral administration, the compounds can be formulated intosolid or liquid preparations such as capsules, pills, tablets, troches,lozenges, melts, powders, solutions, suspensions, or emulsions, and maybe prepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatine typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatine,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, colouring agents, and flavouring agents such as peppermint, oil ofwintergreen, or cherry flavouring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both. Dispersible powders and granules are suitablefor the preparation of an aqueous suspension. They provide the activeingredient in admixture with a dispersing or wetting agent, a suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example those sweetening, flavouringand colouring agents described above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavouring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more colouring agents; one or more flavouringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavouring and colouring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimise or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al., “Compendium of Excipients forParenteral Formulations” PDA Journal of Pharmaceutical Science &Technology 1998, 52(5), 238-311; Strickley, R. G “ParenteralFormulations of Small Molecule Therapeutics Marketed in the UnitedStates (1999)-Part-1” PDA Journal of Pharmaceutical Science & Technology1999, 53(6), 324-349; and Nema, S. et al., “Excipients and Their Use inInjectable Products” PDA Journal of Pharmaceutical Science & Technology1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)

air displacement agents (examples include but are not limited tonitrogen and argon);

antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);

antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);

binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);

buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)

carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)

chelating agents (examples include but are not limited to edetatedisodium and edetic acid)

colourants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);

clarifying agents (examples include but are not limited to bentonite);

emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)

flavourants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);

levigating agents (examples include but are not limited to mineral oiland glycerin);

oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);

penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas)

plasticizers (examples include but are not limited to diethyl phthalateand glycerol);

solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);

stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);

suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));

surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);

suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);

tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);

tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);

tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);

tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);

tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);

tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);

tablet/capsule opaquants (examples include but are not limited totitanium dioxide);

tablet polishing agents (examples include but are not limited to carnubawax and white wax);

thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);

tonicity agents (examples include but are not limited to dextrose andsodium chloride);

viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);and

wetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution: A 5 mg/mL solution of the desired compound of thisinvention can be made using sterile, injectable water, and the pH isadjusted if necessary. The solution is diluted for administration to 1-2mg/mL with sterile 5% dextrose and is administered as an IV infusionover about 60 min.

Lyophilised powder for IV administration: A sterile preparation can beprepared with (i) 100-1000 mg of the desired compound of this inventionas a lyophilised powder, (ii) 32-327 mg/mL sodium citrate, and (iii)300-3000 mg Dextran 40. The formulation is reconstituted with sterile,injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL,which is further diluted with saline or dextrose 5% to 0.2-0.4 mg/mL,and is administered either IV bolus or by IV infusion over 15-60 min.

Intramuscular suspension: The following solution or suspension can beprepared, for intramuscular injection:

-   50 mg/mL of the desired, water-insoluble compound of this invention-   5 mg/mL sodium carboxymethylcellulose-   4 mg/mL TWEEN 80-   9 mg/mL sodium chloride-   9 mg/mL benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared byfilling standard two-piece hard galantine capsules each with 100 mg ofpowdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestibleoil such as soybean oil, cottonseed oil or olive oil is prepared andinjected by means of a positive displacement pump into molten gelatin toform soft gelatin capsules containing 100 mg of the active ingredient.The capsules are washed and dried. The active ingredient can bedissolved in a mixture of polyethylene glycol, glycerin and sorbitol toprepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventionalprocedures so that the dosage unit is 100 mg of active ingredient, 0.2mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage formsmade by conventional and novel processes. These units are taken orallywithout water for immediate dissolution and delivery of the medication.The active ingredient is mixed in a liquid containing ingredient such assugar, gelatin, pectin and sweeteners. These liquids are solidified intosolid tablets or caplets by freeze drying and solid state extractiontechniques. The drug compounds may be compressed with viscoelastic andthermoelastic sugars and polymers or effervescent components to produceporous matrices intended for immediate release, without the need ofwater.

Combination Therapies

The term “combination” in the present invention is used as known topersons skilled in the art and may be present as a fixed combination, anon-fixed combination or kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein thesaid first active ingredient and the said second active ingredient arepresent together in one unit dosage or in a single entity. One exampleof a “fixed combination” is a pharmaceutical composition wherein thesaid first active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein the said first active ingredient and the said secondactive ingredient are present in more than one unit. One example of anon-fixed combination or kit-of-parts is a combination wherein the saidfirst active ingredient and the said second active ingredient arepresent separately. The components of the non-fixed combination orkit-of-parts may be administered separately, sequentially,simultaneously, concurrently or chronologically staggered.

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. The present invention relates also to suchcombinations. For example, the compounds of this invention can becombined with known chemotherapeutic agents or anti-cancer agents, e.g.anti-hyper-proliferative or other indication agents, and the like, aswell as with admixtures and combinations thereof. Other indicationagents include, but are not limited to, anti-angiogenic agents, mitoticinhibitors, alkylating agents, anti-metabolites, DNA-intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymeinhibitors, toposisomerase inhibitors, biological response modifiers, oranti-hormones.

The term “chemotherapeutic anti-cancer agents”, includes but is notlimited to 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin,alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin,amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase,azacitidine, basiliximab, BAY 1000394, belotecan, bendamustine,bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin,bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calciumlevofolinate, capecitabine, carboplatin, carmofur, carmustine,catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil,chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid,clofarabine, copanlisib , crisantaspase, cyclophosphamide, cyproterone,cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib,daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab,deslorelin, dibrospidium chloride, docetaxel, doxifluridine,doxorubicin, doxorubicin+estrone, eculizumab, edrecolomab, elliptiniumacetate, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol,epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol,estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim,fludarabine, fluorouracil, flutamide, formestane, fotemustine,fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin,hydroxycarbamide, I-125 seeds, ibandronic acid, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferonalfa, interferon beta, interferon gamma, ipilimumab, irinotecan,ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan,letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine,lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan,mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methylaminolevulinate, methyltestosterone, mifamurtide, miltefosine,miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide,nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin,oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetinbeta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b,pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide,picibanil, pirarubicin, plerixafor, plicamycin, poliglusam,polyestradiol phosphate, polysaccharide-K, porfimer sodium,pralatrexate, prednimustine, procarbazine, quinagolide, radium-223chloride, raloxifene, raltitrexed, ranimustine, razoxane, refametinib ,regorafenib, risedronic acid, rituximab, romidepsin, romiplostim,sargramostim, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole,sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen,tasonermin, teceleukin, tegafur, tegafur+gimeracil+oteracil, temoporfin,temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin,thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan,toremifene, tositumomab, trabectedin, trastuzumab, treosulfan,tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex,valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine,vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole,yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer,zoledronic acid, zorubicin.

The compounds of the invention may also be administered in combinationwith protein therapeutics. Such protein therapeutics suitable for thetreatment of cancer or other angiogenic disorders and for use with thecompositions of the invention include, but are not limited to, aninterferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonisticmonoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin,anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab,trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1,bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab,rhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35,MT-103, rinfabate, AS-1402, B43-genistein, L-19 basedradioimmunotherapeutics, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322,rhCC10, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine,APC-8024, NGR-hTNF, rhH1.3, IGN-311, Endostatin, volociximab, PRO-1762,lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein,PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab,alpha-particle-emitting radioisotope-(linked lintuzumab, EM-1421,HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7,Javelin—prostate cancer, Javelin—melanoma, NY-ESO-1 vaccine, EGFvaccine, CYT-004-MelQbG10, WT1 peptide, oregovomab, ofatumumab,zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aflibercept,denosumab, vaccine, CTP-37, efungumab, or 131I-chTNT-1/B. Monoclonalantibodies useful as the protein therapeutic include, but are notlimited to, muromonab-CD3, abciximab, edrecolomab, daclizumab,gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab,efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab,daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.

A compound of general formula (1) as defined herein can optionally beadministered in combination with one or more of the following: ARRY-162,ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226,BKM-120, BYL-719, CAL-101, CC-223, CH-5132799, deforolimus, E-6201,enzastaurin, GDC-0032, GDC-0068, GDC-0623, GDC-0941, GDC-0973, GDC-0980,GSK-2110183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027,perifosine, PF-04691502, PF-05212384, PX-866, rapamycin, RG-7167,RO-4987655, RO-5126766, selumetinib, TAK-733, trametinib, triciribine,UCN-01, WX-554, XL-147, XL-765, zotarolimus, ZSTK-474.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,

(2) provide for the administration of lesser amounts of the administeredchemo-therapeutic agents,

(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,

(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,

(5) provide for a higher response rate among treated patients,

(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,

(7) provide a longer time for tumor progression, and/or

(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

Methods of Sensitizing Cells to Radiation

In a distinct embodiment of the present invention, a compound of thepresent invention may be used to sensitize a cell to radiation. That is,treatment of a cell with a compound of the present invention prior toradiation treatment of the cell renders the cell more susceptible to DNAdamage and cell death than the cell would be in the absence of anytreatment with a compound of the invention. In one aspect, the cell istreated with at least one compound of the invention.

Thus, the present invention also provides a method of killing a cell,wherein a cell is administered one or more compounds of the invention incombination with conventional radiation therapy.

The present invention also provides a method of rendering a cell moresusceptible to cell death, wherein the cell is treated with one or morecompounds of the invention prior to the treatment of the cell to causeor induce cell death. In one aspect, after the cell is treated with oneor more compounds of the invention, the cell is treated with at leastone compound, or at least one method, or a combination thereof, in orderto cause DNA damage for the purpose of inhibiting the function of thenormal cell or killing the cell.

In one embodiment, a cell is killed by treating the cell with at leastone DNA damaging agent. That is, after treating a cell with one or morecompounds of the invention to sensitize the cell to cell death, the cellis treated with at least one DNA damaging agent to kill the cell. DNAdamaging agents useful in the present invention include, but are notlimited to, chemotherapeutic agents (e.g., cisplatinum), ionizingradiation (X-rays, ultraviolet radiation), carcinogenic agents, andmutagenic agents.

In another embodiment, a cell is killed by treating the cell with atleast one method to cause or induce DNA damage. Such methods include,but are not limited to, activation of a cell signalling pathway thatresults in DNA damage when the pathway is activated, inhibiting of acell signalling pathway that results in DNA damage when the pathway isinhibited, and inducing a biochemical change in a cell, wherein thechange results in DNA damage. By way of a non-limiting example, a DNArepair pathway in a cell can be inhibited, thereby preventing the repairof DNA damage and resulting in an abnormal accumulation of DNA damage ina cell.

In one aspect of the invention, a compound of the invention isadministered to a cell prior to the radiation or other induction of DNAdamage in the cell. In another aspect of the invention, a compound ofthe invention is administered to a cell concomitantly with the radiationor other induction of DNA damage in the cell. In yet another aspect ofthe invention, a compound of the invention is administered to a cellimmediately after radiation or other induction of DNA damage in the cellhas begun.

In another aspect, the cell is in vitro. In another embodiment, the cellis in vivo.

As mentioned supra, the compounds of the present invention havesurprisingly been found to effectively inhibit mutatedisocitratdehydrogenase 1 (mIDH1 R132H) and may therefore be used for thetreatment or prophylaxis of diseases of uncontrolled cell growth,proliferation and/or survival, inappropriate cellular immune responses,or inappropriate cellular inflammatory responses, or diseases which areaccompanied with uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses, particularly in which the uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses areaffected by inhibition of mutated isocitratdehydrogenase 1 (mIDH1R132H), such as, for example, haematological tumours, solid tumours,and/or metastases thereof, e.g. leukaemias and myelodysplastic syndrome,malignant lymphomas, head and neck tumours including brain tumours andbrain metastases, tumours of the thorax including non-small cell andsmall cell lung tumours, gastrointestinal tumours, endocrine tumours,mammary and other gynaecological tumours, urological tumours includingrenal, bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

In accordance with another aspect therefore, the present inventioncovers a compound of general formula (I), or a stereoisomer, a tautomer,an N-oxide, a hydrate, a solvate, or a salt thereof, particularly apharmaceutically acceptable salt thereof, or a mixture of same, asdescribed and defined herein, for use in the treatment or prophylaxis ofa disease, as mentioned supra.

Another particular aspect of the present invention is therefore the useof a compound of general formula (I), described supra, or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, particularly a pharmaceutically acceptable salt thereof, or amixture of same, for the prophylaxis or treatment of a disease.

Another particular aspect of the present invention is therefore the useof a compound of general formula (I) described supra for manufacturing apharmaceutical composition for the treatment or prophylaxis of adisease.

The diseases referred to in the two preceding paragraphs are diseases ofuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses, or diseases which are accompanied with uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses, such as,for example, haematological tumours, solid tumours, and/or metastasesthereof, e.g. leukaemias and myelodysplastic syndrome, malignantlymphomas, head and neck tumours including brain tumours and brainmetastases, tumours of the thorax including non-small cell and smallcell lung tumours, gastrointestinal tumours, endocrine tumours, mammaryand other gynaecological tumours, urological tumours including renal,bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

The term “inappropriate” within the context of the present invention, inparticular in the context of “inappropriate cellular immune responses,or inappropriate cellular inflammatory responses”, as used herein, is tobe understood as meaning a response which is less than, or greater thannormal, and which is associated with, responsible for, or results in,the pathology of said diseases.

Preferably, the use is in the treatment or prophylaxis of diseases,wherein the diseases are haemotological tumours, solid tumours and/ormetastases thereof.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce apoptosis. This method comprises administering to amammal in need thereof, including a human, an amount of a compound ofthis invention, or a pharmaceutically acceptable salt, isomer,polymorph, metabolite, hydrate, solvate or ester thereof; etc. which iseffective to treat the disorder.

Hyperproliferative disorders include but are not limited, e.g.,psoriasis, keloids, and other hyperplasias affecting the skin, benignprostate hyperplasia (BPH), solid tumours, such as cancers of thebreast, respiratory tract, brain, reproductive organs, digestive tract,urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid andtheir distant metastases. Those disorders also include lymphomas,sarcomas, and leukaemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypophtalmic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, anaplastic astrocytoma, diffuseastrocytoma, glioblastoma, oligodendroglioma, secondary glioblastomamultiforme as well as neuroectodermal and pineal tumour.

Tumours of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumours of the female reproductiveorgans include, but are not limited to endometrial, cervical, ovarian,vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumours of the digestive tract include, but are not limited to anal,colon, colorectal, oesophageal, gallbladder, gastric, pancreatic,rectal, small-intestine, and salivary gland cancers.

Tumours of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma. Examples of liver cancers include, but are not limitedto hepatocellular carcinoma (liver cell carcinomas with or withoutfibrolamellar variant), cholangiocarcinoma (intrahepatic bile ductcarcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855],neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumour enlargement and metastasis. Moreover,the growth of new blood and lymph vessels in a tumour provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death or apoptosis of such cell types.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Preferably, the diseases of said method are haematological tumours,solid tumour and/or metastases thereof.

The compounds of the present invention can be used in particular intherapy and prevention, i.e. prophylaxis, of tumour growth andmetastases, especially in solid tumours of all indications and stageswith or without pre-treatment of the tumour growth.

Methods of testing for a particular pharmacological or pharmaceuticalproperty are well known to persons skilled in the art.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

Biological Assays:

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

Mutant IDH1 R132H Biochemical Assay

mIDH1 catalyzes the NADPH-dependent reduction of alpha-ketoglutarate(α-KG) to (2R)-2-hydroxyglutarate (2-HG). NADPH consumption was measuredby luminescent readout.

The biochemical reactions were performed at 32° C. in 384-well platesusing a reaction volume of 41 μl and the following assay bufferconditions: 50 mM Tris pH 7.5, 100 mM NaCl, 20 mM MgCl₂, 0.05% BSA,0.01% Brij, 1 pM NADPH, and 250 μM α-KG. The IDH1 R132H enzyme was usedin a final concentration of 1.5 nM. Test compounds were used in aconcentration range between 0.002 and 10 μM. The final DMSOconcentration was 2.4%.

The reaction was incubated for 30 minutes, then 40 μl of detection mix(0.75 μg/ml Luciferase, 0.02 U/ml Oxidoreductase, 4 μg/ml FMN, 2 μl/mlDecanal/Ethanol, 50 mM Tris pH 7.5, 0.5% Glycerin, 0.01% Tween-20, 0.05%BSA) was added. Luminescence was measured on a luminescent reader (10seconds measuring time, 1 second integration period, 30% sensitivity).The decrease in luminescence is proportional to mIDH1 activity. IC₅₀values are determined by interpolation from plots of relativeluminescence versus inhibitor concentration.

TABLE 2 IC₅₀ values of selected examples in mutant IDH1 R132Hbiochemical assay Example Mutant IDH1 R132H IC₅₀ [μM] 2-1 0.12 2-1-10.24 2-1-2 0.07 2-2 0.07 2-3 0.46 2-4 0.08 2-5 0.09 2-5-1 0.67 2-5-21.54 2-7 0.11 2-8 0.13 2-9 0.18 2-10 0.14 2-10-1 0.30 2-10-2 0.14 2-110.21 2-12 0.10 2-12-1 4.3 2-12-2 1.6 2-13 1.1 2-13-1 0.24 2-13-2 1.02-14 1.3 2-15 1.5 2-16 0.29 2-16-1 7.8 2-16-2 0.78 2-17 0.44 2-18 4.02-19 1.9 2-20 10 2-21 10 2-21-1 1.1 2-21-2 0.29 2-22 0.77 2-23 10 2-23-110 2-23-2 0.18 2-24 10 2-24-1 10 2-24-2 0.14 2-25 0.13 2-26 0.22 2-271.8 2-28 0.07 2-29 4 2-30 0.12 2-31 0.39 2-32 10 2-33 0.67 2-34 0.182-35 0.24 2-36 0.014 2-37 0.03

Mutant IDH1 Cellular Assay

Levels of (2R)-2-hydroxyglutarate (2HG) were measured in medium of acell line with overexpression of mutated isocitrate dehydrogenase (mIDH)protein. mIDH catalyzes the NADPH-dependent reduction ofalpha-ketoglutarate to 2-HG. Cells (LN229 R132H, Mohrenz et al.,Apoptosis (2013) 18:1416-1425) were grown in DMEM containing 10% FCS.They were harvested by trypsin and seeded into 96-well plates. Cellswere incubated overnight at 37° C. in 5% CO₂. The next day testcompounds were added to each cell well. The final concentration of DMSOwas 0.1% and DMSO controls were included. The plates were then placed inan incubator for 24 hours.

2-HG was measured according to Balss et al. (Acta Neuropathol (2012)124: 883-891). Briefly, HClO₄ was added to each well and the plates werecentrifuged. Aliquots are removed and incubated with hydroxyglutaratedehydrogenase (HGDH), diaphorase, NAD+, and resazurin. The conversion ofresazurin to resorufin was detected by fluorescence spectroscopy at Ex540 nm Em 600 nm. The increase in fluorescence is proportional to 2-HGproduction. IC₅₀ values are determined by interpolation from plots ofrelative fluorescence vs inhibitor concentration.

TABLE 3 IC₅₀ values of selected examples in mutant IDH1 cellular assayExample Mutant IDH1 IC₅₀ [μM] 2-1 0.90 2-2 0.36 2-4 0.60 2-5 4 2-5-2 1.52-7 1.2 2-8 2.0 2-9 2.0 2-10 2.0 2-10-1 10 2-10-2 3.0 2-11 2.8 2-12 8.02-13 5.0 2-19 10 2-20 4.0 2-21-1 10 2-21-2 2.5 2-22 2.5 2-23-2 10 2-24-27.0 2-26 10 2-28 0.20 2-29 2.7 2-30 1.5 2-36 0.022 2-37 0.25

1. A compound of formula (I)

in which: R¹ represents a halogen atom or group selected from:C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, cyano,(C₁-C₆-alkyl)-S—, and (C₁-C₆-haloalkyl)-S—; R² represents a hydrogenatom; R³ represents a hydrogen atom; R⁴ represents a hydrogen atom; R⁵represents a phenyl or heteroaryl group; wherein said group isoptionally substituted, with one or more substituents, which areindependently of each other selected from: halo-, cyano, C₁-C₆-alkyl,C₃-C₆-cycloalkyl, ₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, nitro, R¹³O—, R¹³S—,R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,R¹³OC(═O)—(C₁-C₆-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-,R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-,(C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂—,(C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³, —C(═O)N(R¹⁴)R¹⁵,—C(═O)N(R¹⁴)S(═O)₂R¹⁶, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶, —N(R¹⁴)C(═O)R¹⁷,—N(R¹⁴)S(═O)₂R¹⁶, —S(═O)₂OR¹³, and —S(═O)₂N(R¹⁴)R¹⁵; R⁶ represents ahydrogen atom or a halogen atom or group selected from: C₁-C₆-alkyl, andC₁-C₆-alkoxy; R⁷ represents a hydrogen atom; R⁸ represents a C₁-C₃-alkylgroup; R⁹, R¹⁰, and R¹¹ are independently of each other selected from:hydrogen and C₁-C₃-alkyl; R¹² represents a hydrogen atom; R¹³ representsa hydrogen atom or a group selected from: C₁-C₆-alkyl, C₃-C₆-cycloalkyl,HO—(C₂-C₆-alkyl)-, and (C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-; R¹⁴ and R¹⁵ areindependently of each other selected from: hydrogen, C₁-C₆-alkyl,C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-, (C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-,C₁-C₆-haloalkyl, H₂N—(C₂-C₆-alkyl)-, (C₁-C₃-alkyl)N(H)(C₂-C₆-alkyl)-,(C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-, R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to6-membered heterocycloalkyl, phenyl, heteroaryl, phenyl-(C₁-C₆-alkyl)-,and heteroaryl-(C₁-C₆-alkyl)-; wherein phenyl and heteroaryl groups areoptionally substituted with one or two substituents, which areindependently of each other selected from: C₁-C₃-alkyl,C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and —C(═O)NH₂; or R¹⁴ andR¹⁵ together with the nitrogen atom to which they are attached form a4-6-membered heterocycloalkyl; said 4-6-membered heterocycloalkyl beingoptionally substituted with one substituent selected from: C₁-C₃-alkyl,C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyloxy, amino, hydroxy, halogen, and cyano; or said4-6-membered heterocycloalkyl being optionally substituted with one ortwo halogen atoms; R¹⁶ represents a hydrogen atom or a group selectedfrom: C₁-C₆-alkyl, HO—(C₁-C₆-alkyl)-, C₃-C₆-cycloalkyl,HO—(C₃-C₆-cycloalkyl)-, C₁-C₆-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-,phenyl, heteroaryl, and 4- to 6-membered heterocycloalkyl; whereinphenyl and heteroaryl groups are optionally substituted with one or twosubstituents, which are independently of each other selected from:C₁-C₃-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵; R¹⁷ represents a group selected from: —N(R¹⁴)R¹⁵ andC₁-C₆-alkoxy; or a stereoisomer, a tautomer, an N-oxide, a hydrate, asolvate, or a salt thereof, or a mixture of same.
 2. The compoundaccording to claim 1, wherein: R¹ represents a group selected from:C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy,(C₁-C₃-alkyl)-S—, and (C₁-C₃-haloalkyl)-S—; or a stereoisomer, atautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or amixture of same.
 3. The compound according to claim 1, wherein: R¹represents a group selected from: C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, and(C₁-C₃-haloalkyl)-S—; or a stereoisomer, a tautomer, an N-oxide, ahydrate, a solvate, or a salt thereof, or a mixture of same.
 4. Thecompound according to claim 1, wherein: R⁵ represents a phenyl orheteroaryl group; wherein said group is optionally substituted, with oneor more substituents, which are independently of each other selectedfrom: halo-, cyano, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl,C₁-C₆-haloalkoxy, nitro, R¹³O—, R¹³S—, R¹³OC(═O)—(C₁-C₆-alkyl)-,R¹³OC(═O)—(C₂-C₆-alkenyl)-, R¹³OC(═O)—(C₁-C₆-alkoxy)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-, R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-, (C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—,(C₁-C₆-alkyl)-S(═O)₂—, (C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³,—C(═O)N(R¹⁴)R¹⁵, —C(═O)N(R¹⁴)S(═O)₂R¹⁶, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶,—N(R¹⁴)C(═O)R¹⁷, —N(R¹⁴)S(═O)₂R¹⁶, —S(═O)₂OR¹³, and —S(═O)₂N(R¹⁴)R¹⁵;wherein said heteroaryl group is selected from: thienyl, furanyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,thia-4H-pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, andtriazinyl; or a stereoisomer, a tautomer, an N-oxide, a hydrate, asolvate, or a salt thereof, or a mixture of same.
 5. The compoundaccording to claim 1, wherein: R⁵ represents a phenyl or heteroarylgroup; wherein said group is optionally substituted, with one or moresubstituents, which are independently of each other selected from:halo-, cyano, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl,C₁-C₆-haloalkoxy, nitro, R¹³O—, R¹³S—, R¹³OC(═O)—(C₁-C₆-alkyl)-,R¹³OC(═O)—(C₂-C₆-alkenyl)-, R¹³OC(═O)—(C₁-C₆-alkoxy)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-, R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-, (C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—,(C₁-C₆-alkyl)-S(═O)₂—, (C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³,—C(═O)N(R¹⁴)R¹⁵, —C(═O)N(R¹⁴)S(═O)₂R¹⁶, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶,—N(R¹⁴)C(═O)R¹⁷, —N(R¹⁴)S(═O)₂R¹⁶, —S(═O)₂OR¹³, and —S(═O)₂N(R¹⁴)R¹⁵;wherein said heteroaryl group is selected from: oxazolyl, pyrazolyl,oxadiazolyl, triazolyl, tetrazolyl, and pyridinyl or a stereoisomer, atautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or amixture of same.
 6. The compound according to claim 1, wherein R⁵represents a phenyl or heteroaryl group; wherein said group isoptionally substituted, with one or more substituents, which areindependently of each other selected from: halo-, C₁-C₆-alkyl,C₁-C₆-haloalkyl, R¹³O—, —C(═O)OR¹³, and —C(═O)N(R¹⁴)R¹⁵; wherein saidheteroaryl group is selected from: thienyl, furanyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, tetrazolyl, thiadiazolyl, thia-4H-pyrazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl; or a stereoisomer, atautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or amixture of same.
 7. The compound according to claim 1, wherein: R⁵represents a phenyl or heteroaryl group; wherein said group isoptionally substituted, with one or more substituents, which areindependently of each other selected from: halo-, C₁-C₆-alkyl,C₁-C₆-haloalkyl, R¹³O—, —C(═O)OR¹³, and —C(═O)N(R¹⁴)R¹⁵; wherein saidheteroaryl group is selected from: oxazolyl, pyrazolyl, oxadiazolyl,triazolyl, tetrazolyl, and pyridinyl; or a stereoisomer, a tautomer, anN-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.8. The compound according to claim 1, wherein: R⁶ represents a hydrogenatom or a halogen atom or group selected from: C₁-C₃-alkyl, andC₁-C₃-alkoxy; or a stereoisomer, a tautomer, an N-oxide, a hydrate, asolvate, or a salt thereof, or a mixture of same.
 9. The compoundaccording to claim 1, wherein: R⁶ represents a hydrogen atom or a methylgroup; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate,or a salt thereof, or a mixture of same.
 10. The compound according toclaim 1, wherein: R⁸ represents a methyl group, R⁹ represents a hydrogenatom, R¹⁰ represents a methyl group, and R¹¹ represents a methyl group;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.
 11. The compound according to claim1, wherein: R⁸ represents a methyl group, R⁹ represents a methyl group,R¹⁰ represents a methyl group, and R¹¹ represents a methyl group; or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, or a mixture of same.
 12. The compound according to claim 1,wherein: R¹³ represents a hydrogen atom or a C₁-C₃-alkyl group; or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, or a mixture of same.
 13. The compound according to claim 1,wherein: R¹⁴ and R¹⁵ are independently of each other selected from:hydrogen, C₁-C₆-alkyl, and C₃-C₆-cycloalkyl; or a stereoisomer, atautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or amixture of same.
 14. The compound according to claim 1, wherein: R¹⁴representa a hydrogen atom and R¹⁵ represents a hydrogen atom; or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, or a mixture of same.
 15. The compound according to claim 1,which is selected from the group consisting of:5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;3-[2-{[4-(trifluoromethoxy)phenyl]amino}-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-5-yl]benzoicacid;3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzoicacid; 3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzoic acid;4-[2-{[4-(trifluoromethoxy)phenyl]amino}-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-5-yl]benzoicacid;4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzoicacid;4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzoicacid;5-(1H-pyrazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(1H-pyrazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1H-pyrazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1,3-dimethyl-1H-pyrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(1,3-dimethyl-1H-pyrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1,3-dimethyl-1H-pyrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3-methyl-1H-pyrazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(3-methyl-1H-pyrazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3-methyl-1H-pyrazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1H-pyrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(1H-pyrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1H-pyrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;3-[2-{[4-(trifluoromethoxy)phenyl]amino}-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-5-yl]benzamide;3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzamide;3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzamide;5-(1,3-dimethyl-1H-pyrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(1,3-dimethyl-1H-pyrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1,3-dimethyl-1H-pyrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1-methyl-1H-pyrazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(1-methyl-1H-pyrazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1-methyl-1H-pyrazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(2-methoxypyridin-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(2-methoxypyridin-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(2-methoxypyridin-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;methyl3-[2-{[4-(trifluoromethoxy)phenyl]amino}-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-5-yl]benzoate;methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzoate;methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzoate;5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;4-[2-{[4-(trifluoromethoxy)phenyl]amino}-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-5-yl]benzamide;4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzamide;4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzamide;methyl4-[2-{[4-(trifluoromethoxy)phenyl]amino}-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-5-yl]benzoate;methyl4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzoate;methyl4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)benzoate;N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzimidazol-2-amine;N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzimidazol-2-amine;N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzimidazol-2-amine;5-(1-methyl-1H-pyrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(1-methyl-1H-pyrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1-methyl-1H-pyrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1H-pyrazol-5-yl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(1H-pyrazol-5-yl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1H-pyrazol-5-yl)-N-{4-[(trifluoromethyl)sulfanyl]phenyl}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethyl)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethyl)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethyl)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-[4-(trifluoromethyl)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-[4-(trifluoromethyl)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-[4-(trifluoromethyl)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(5-Methyl-1,3,4-oxadiazol-2-yl)-1-(3,3,5,5-tetramethylcyclohexyl)-N-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-amine;5-(5-Methyl-1,2,4-oxadiazol-3-yl)-1-(3,3,5,5-tetramethylcyclohexyl)-N-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-amine;5-(1H-tetrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(1H-tetrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(1H-tetrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;1-(3,3,5,5-tetramethylcyclohexyl)-5-(1H-tetrazol-5-yl)-N-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-amine;5-(3,5-dimethyl-1H-pyrazol-4-yl)-6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-N-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-amine;6-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)-1-(3,3,5,5-tetramethylcyclohexyl)-N-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-amine;5-(5-methyl-1,3,4-oxadiazol-2-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(5-methyl-1,3,4-oxadiazol-2-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(5-methyl-1,3,4-oxadiazol-2-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-difluoro-4-methoxyphenyl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(3,5-difluoro-4-methoxyphenyl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3,5-difluoro-4-methoxyphenyl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;2,6-difluoro-4-[2-{[4-(trifluoromethoxy)phenyl]amino}-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-5-yl]phenol;2,6-difluoro-4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)phenol;2,6-difluoro-4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)phenol;2,6-dimethyl-4-[2-{[4-(trifluoromethoxy)phenyl]amino}-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-5-yl]phenol;2,6-dimethyl-4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)phenol;2,6-dimethyl-4-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)phenol;5-(3-ethoxy-5-methyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-(3,3,5-trimethylcyclohexyl)-1H-benzimidazol-2-amine;5-(3-ethoxy-5-methyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-(3-ethoxy-5-methyl-1,2-oxazol-4-yl)-N-[4-(trifluoromethoxy)phenyl]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine;5-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,3-oxazolidine-2,4-dione;and5-[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]-1,2-oxazol-3-ol;or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.
 16. A method of preparing a compoundof general formula (I) according to claim 1, said method comprising thestep of allowing an intermediate compound of general formula (VI):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) according to claim 1, to react with acompound of general formula (III):

in which R¹, R² and R³ are as defined for the compound of generalformula (I) according to claim 1, thereby giving a compound of generalformula (I):

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are asdefined for the compound of general formula (I) according to claim 1.17. A method of preparing a compound of general formula (I) according toclaim 1, said method comprising the step of allowing an intermediatecompound of general formula (IV):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) according to claim 1, to react with acompound of general formula (V):

in which R¹, R², R³ and R¹² are as defined for the compound of generalformula (I) according to claim 1, thereby giving a compound of generalformula (I):

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are asdefined for the compound of general formula (I) according to claim 1.18. A method of preparing a compound of general formula (I) according toclaim 1, said method comprising the step of allowing an intermediatecompound of general formula (II):

in which R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined for thecompound of general formula (I) according to claim 1, and LG is aleaving group, to react with a compound of general formula (VII):R⁵—Y   (VII) in which R⁵ is as defined as for the compound of generalformula (I) according to claim 1 and Y is a group enabling palladiumcatalysed coupling reactions; thereby giving a compound of generalformula (I):

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are asdefined for the compound of general formula (I) according to claim 1.19. (canceled)
 20. A pharmaceutical composition comprising a compound ofgeneral formula (I), or a stereoisomer, a tautomer, an N-oxide, ahydrate, a solvate, or a salt thereof, or a mixture of same, accordingto claim 1, and a pharmaceutically acceptable diluent or carrier.
 21. Apharmaceutical combination comprising: one or more first activeingredients selected from a compound of general formula (I) according toclaim 1, or a stereoisomer, a tautomer, an N-oxide, a hydrate, asolvate, or a salt thereof, or a mixture of same; and one or more secondactive ingredients selected from chemotherapeutic anti-cancer agents.22. (canceled)
 23. A method for the prophylaxis or treatment of adisease, comprising administering to a patient in need thereof apharmaceutically effective amount of a compound of general formula (I),or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same, according to claim
 1. 24. The methodaccording to claim 23, wherein said disease is a disease of uncontrolledcell growth, proliferation and/or survival, an inappropriate cellularimmune response, or an inappropriate cellular inflammatory response.25-27. (canceled)
 28. The method according to claim 23, wherein saiddisease is a haematological tumour, a solid tumour, or metastasesthereof.
 29. The method according to claim 23, wherein said disease isleukaemia, myelodysplastic syndrome, malignant lymphoma, a head and necktumour, a brain tumour, a tumour of the thorax, a non-small cell lungtumour, a small cell lung tumour, a gastrointestinal tumour, anendocrine tumour, a mammary tumour, a gynaecological tumour, aurological tumour, a renal tumour, a bladder tumour, a prostate tumour,a skin tumour, sarcoma, or metastases thereof.